Genes

2024

Jump to: 2023, 2022, 2021

15 pages, 2057 KiB

Open AccessReview

Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations

by Masaki Watanabe and Nobuya Sasaki

Genes 2024, 15(7), 894; https://doi.org/10.3390/genes15070894 - 8 Jul 2024

Viewed by 1401

Abstract

Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 [...] Read more.

Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 and IARS2 have recently been linked to mitochondrial diseases. This review aims to explore the relationship between IARS1 and IARS2 and these diseases, providing a comprehensive overview of their association with mitochondrial diseases. Mutations in IARS1 cause weak calf syndrome in cattle and mitochondrial diseases in humans, leading to growth retardation and liver dysfunction. Mutations in IARS2 are associated with Leigh syndrome, craniosynostosis and abnormal genitalia syndrome. Future research is expected to involve genetic analysis of a larger number of patients, identifying new mutations in IARS1 and IARS2, and elucidating their impact on mitochondrial function. Additionally, genetically modified mice and the corresponding phenotypic analysis will serve as powerful tools for understanding the functions of these gene products and unraveling disease mechanisms. This will likely promote the development of new therapies and preventive measures. Full article

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2023

Jump to: 2024, 2022, 2021

10 pages, 14521 KiB

Open AccessArticle

Diprosopus: A Rare Case of Craniofacial Duplication and a Systematic Review of the Literature

by Viola Trevisani, Eleonora Balestri, Manuela Napoli, Stefano Giuseppe Caraffi, Maria Chiara Baroni, Francesca Peluso, Anna Colonna, Lorenzo Iughetti, Giancarlo Gargano, Andrea Superti-Furga and Livia Garavelli

Genes 2023, 14(9), 1745; https://doi.org/10.3390/genes14091745 - 31 Aug 2023

Cited by 2 | Viewed by 4784

Abstract

In 1990, Gorlin et al. described four types of craniofacial duplications: (1) single mouth with duplication of the maxillary arch; (2) supernumerary mouth laterally placed with rudimentary segments; (3) single mouth with replication of the mandibular segments; and (4) true facial duplication, namely [...] Read more.

In 1990, Gorlin et al. described four types of craniofacial duplications: (1) single mouth with duplication of the maxillary arch; (2) supernumerary mouth laterally placed with rudimentary segments; (3) single mouth with replication of the mandibular segments; and (4) true facial duplication, namely diprosopus. We describe a newborn born with wide-spaced eyes, a very broad nose, and two separate mouths. Workup revealed the absence of the corpus callosum and the presence of a brain midline lipoma, wide sutures, and a Chiari I malformation with cerebellar herniation. We conducted a systematic review of the literature and compared all the cases described as diprosopus. In 96% of these, the central nervous system is affected, with anencephaly being the most commonly associated abnormality. Other associated anomalies include cardiac malformations (86%), cleft palate (63%), diaphragmatic hernia (13%), and disorder of sex development (DSD) (13%). Although the facial features are those that first strike the eye, the almost obligate presence of cerebral malformations suggests a disruptive event in the cephalic pole of the forming embryo. No major monogenic contribution has been recognized today for this type of malformation. Full article

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13 pages, 2280 KiB

Open AccessArticle

Split Hand-Foot and Deafness in a Patient with 7q21.13-q21.3 Deletion Not Including the DLX5/6 Genes

by Irene Ambrosetti, Laura Bernardini, Marzia Pollazzon, Maria Grazia Giuffrida, Valentina Guida, Francesca Peluso, Maria Chiara Baroni, Valeria Polizzi, Manuela Napoli, Simonetta Rosato, Gabriele Trimarchi, Chiara Gelmini, Stefano Giuseppe Caraffi, Anita Wischmeijer, Daniele Frattini, Antonio Novelli and Livia Garavelli

Genes 2023, 14(8), 1526; https://doi.org/10.3390/genes14081526 - 26 Jul 2023

Cited by 1 | Viewed by 1590

Abstract

Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most [...] Read more.

Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the DLX5/DLX6 genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the DLX5/6 genes, but including exons 15 and 17 of DYNC1I1, known to act as exonic enhancers (eExons) of the DLX5/6 genes. We further demonstrated the role of DYNC1I1 eExons in regulating DLX5/6 expression by means of showing a reduced expression of the DLX5/6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that DLX5/6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations. Full article

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13 pages, 6051 KiB

Open AccessArticle

Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome

by Emanuele Coccia, Lara Valeri, Roberta Zuntini, Stefano Giuseppe Caraffi, Francesca Peluso, Luca Pagliai, Antonietta Vezzani, Zaira Pietrangiolillo, Francesco Leo, Nives Melli, Valentina Fiorini, Andrea Greco, Francesca Romana Lepri, Elisa Pisaneschi, Annabella Marozza, Diana Carli, Alessandro Mussa, Francesca Clementina Radio, Beatrice Conti, Maria Iascone, Giancarlo Gargano, Antonio Novelli, Marco Tartaglia, Orsetta Zuffardi, Maria Francesca Bedeschi and Livia Garavelli Show full author list Hide full author list

Genes 2023, 14(3), 549; https://doi.org/10.3390/genes14030549 - 22 Feb 2023

Cited by 5 | Viewed by 3509

Abstract

Pathogenic variants in RASA1 are typically associated with a clinical condition called “capillary malformation-arteriovenous malformation” (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in [...] Read more.

Pathogenic variants in RASA1 are typically associated with a clinical condition called “capillary malformation-arteriovenous malformation” (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far. Here, we report four pediatric cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. Polyhydramnios, non-immune hydrops fetalis and chylothorax are only a few possible aspects of this condition, but a correct interpretation of these prenatal signs is essential due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in family members carrying the same RASA1 variant. Full article

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20 pages, 475 KiB

Open AccessSystematic Review

Status Epilepticus in Chromosomal Disorders Associated with Epilepsy: A Systematic Review

by Luca Bergonzini, Jacopo Pruccoli, Ilaria Pettenuzzo, Rosa Pugliano, Luca Soliani, Anna Fetta and Duccio Maria Cordelli

Genes 2023, 14(2), 299; https://doi.org/10.3390/genes14020299 - 23 Jan 2023

Viewed by 2377

Abstract

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding [...] Read more.

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding SE occurrence in these patients is lacking. A systematic scoping review was conducted to outline current literature evidence about clinical features, treatments, and outcomes of SE in pediatric and adult patients with CDAE. A total of 373 studies were identified with the initial search; 65 of these were selected and regarded as SE in Angelman Syndrome (AS, n = 20), Ring 20 Syndrome (R20, n = 24), and other syndromes (n = 21). Non-convulsive status epilepticus (NCSE) is frequently observed in AS and R20. No specific, targeted therapies for SE in CDAE are available to date; anecdotal reports about SE treatment are described in the text, as well as various brief- and long-term outcomes. Further evidence is needed to precisely portray the clinical features, treatment options, and outcomes of SE in these patients. Full article

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15 pages, 304 KiB

Open AccessArticle

Insights into the Cardiac Phenotype in 9p Deletion Syndrome: A Multicenter Italian Experience and Literature Review

by Flaminia Pugnaloni, Roberta Onesimo, Rita Blandino, Carolina Putotto, Paolo Versacci, Angelica Bibiana Delogu, Chiara Leoni, Valentina Trevisan, Ileana Croci, Federica Calì, Maria Cristina Digilio, Giuseppe Zampino, Bruno Marino and Giulio Calcagni

Genes 2023, 14(1), 146; https://doi.org/10.3390/genes14010146 - 5 Jan 2023

Cited by 1 | Viewed by 3024

Abstract

Chromosome 9p deletion syndrome is a rare autosomal dominant disorder presenting with a broad spectrum of clinical features, including congenital heart defects (CHDs). To date, studies focused on a deep characterization of cardiac phenotype and function associated with this condition are lacking. We [...] Read more.

Chromosome 9p deletion syndrome is a rare autosomal dominant disorder presenting with a broad spectrum of clinical features, including congenital heart defects (CHDs). To date, studies focused on a deep characterization of cardiac phenotype and function associated with this condition are lacking. We conducted a multicentric prospective observational study on a cohort of 10 patients with a molecular diagnosis of 9p deletion syndrome, providing a complete cardiological assessment through conventional echocardiography and tissue Doppler imaging echo modality. As a result, we were able to demonstrate that patients with 9p deletion syndrome without major CHDs may display subclinical cardiac structural changes and left-ventricle systolic and diastolic dysfunction. Albeit needing validation in a larger cohort, our findings support the idea that a complete cardiac assessment should be performed in patients with 9p deletion syndrome and should be integrated in the context of a long-term follow-up. Full article

2022

Jump to: 2024, 2023, 2021

10 pages, 1533 KiB

Open AccessCase Report

Two Novel Variants of WDR26 in Chinese Patients with Intellectual Disability

by Jiacheng Hu, Mingming Xu, Xiaobo Zhu and Yu Zhang

Genes 2022, 13(5), 813; https://doi.org/10.3390/genes13050813 - 2 May 2022

Cited by 4 | Viewed by 2801

Abstract

Skraban-Deardorff syndrome is a rare autosomal dominant genetic disease caused by variants in the WDR26 gene. Here, we report two Chinese patients diagnosed with Skraban-Deardorff syndrome caused by novel de novo, heterozygous pathogenic WDR26 variants c.977delA (p. 12 N326Ifs*2) and c.1020-2A>G (p. R340Sfs*29). [...] Read more.

Skraban-Deardorff syndrome is a rare autosomal dominant genetic disease caused by variants in the WDR26 gene. Here, we report two Chinese patients diagnosed with Skraban-Deardorff syndrome caused by novel de novo, heterozygous pathogenic WDR26 variants c.977delA (p. 12 N326Ifs*2) and c.1020-2A>G (p. R340Sfs*29). Their clinical features were characterized by intellectual disability (ID), developmental delay, abnormal facial features and the absence of early-onset seizure, which expands the phenotype spectrum associated with Skraban-Deardorff syndrome. By comparing our cases with current reported cases of WDR26-related intellectual disability, we suggest that developmental delay, particularly in speech, and facial features including rounded palpebral fissures, depressed nasal root, full nasal tip and abnormal gums, represent the prominent clinical phenotypes for diagnosis of Skraban-Deardorff syndrome. Together, WDR26 variants and 1q41q42 deletions should feature prominently on the differential diagnosis of ID with distinctive facial features. Full article

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10 pages, 2576 KiB

Open AccessArticle

A Novel de Novo Variant in 5′ UTR of the NIPBL Associated with Cornelia de Lange Syndrome

by Yonghua Chen, Qingqing Chen, Ke Yuan, Jianfang Zhu, Yanlan Fang, Qingfeng Yan and Chunlin Wang

Genes 2022, 13(5), 740; https://doi.org/10.3390/genes13050740 - 22 Apr 2022

Cited by 2 | Viewed by 2307

Abstract

Background: Cornelia de Lange syndrome (CdLS) is a genetic syndrome characterized by intellectual disability, special facial features, growth retardation, feeding difficulties, and multiple organ system abnormalities. NIPBL variants occur in approximately 80% of CdLS cases. Aims: We report a novel de novo heterozygous [...] Read more.

Background: Cornelia de Lange syndrome (CdLS) is a genetic syndrome characterized by intellectual disability, special facial features, growth retardation, feeding difficulties, and multiple organ system abnormalities. NIPBL variants occur in approximately 80% of CdLS cases. Aims: We report a novel de novo heterozygous pathogenic variant in the NIPBL and its association with CdLS. We also examined the key regulatory sequences of the 5′ untranslated region in NIPBL mRNA. Few studies have reported mutation sites in the 5′ untranslated region (UTR) of the NIPBL that result in CdLS. Methods: The patient’s medical history, clinical manifestations, physical examination, laboratory examination, Griffiths development assessment scale—Chinese version, and cardiac B-ultrasound were examined. Mutation screening was conducted using trio whole exome sequencing (trio-WES) and Sanger sequencing. Quantitative PCR was performed to measure the NIPBL expression in peripheral blood mononuclear cells. A Dual-Luciferase reporter assay was conducted to evaluate the transcription of truncated mutants. Results: The proband showed characteristics of CdLS including thick eyebrows, a concave nasal ridge, long and smooth philtrum, downturned corners of the mouth, intellectual disability, postnatal growth retardation, and a short fifth toe. A novel de novo heterozygous pathogenic variant in the NIPBL (c.-467C > T) was identified. A Dual-Luciferase reporter gene assay showed that SPO1 (-490 bp to -360 bp) and SPO3 (-490 bp to -401 bp) induced the highest activity. Conclusions: We found a novel de novo heterozygous pathogenic variant (c.-467C > T) in the NIPBL resulting in CdLS. Our findings expand the spectrum of pathogenic mutations for CdLS. Our in vitro experiments elucidated important regulatory sequences in the 5′ UTR of the NIPBL. Full article

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14 pages, 3431 KiB

Open AccessEditor’s ChoiceCase Report

MCPH1: A Novel Case Report and a Review of the Literature

by Stefano Giuseppe Caraffi, Marzia Pollazzon, Muhammad Farooq, Ambrin Fatima, Lars Allan Larsen, Roberta Zuntini, Manuela Napoli and Livia Garavelli

Genes 2022, 13(4), 634; https://doi.org/10.3390/genes13040634 - 2 Apr 2022

Cited by 5 | Viewed by 3083

Abstract

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly [...] Read more.

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, MCPH1 or Microcephalin, encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on MCPH1 function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1–8 of MCPH1. We compare the patients’ characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution. Full article

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13 pages, 594 KiB

Open AccessCase Report

Osteogenesis Imperfecta/Ehlers–Danlos Overlap Syndrome and Neuroblastoma—Case Report and Review of Literature

by Letteria Anna Morabito, Anna Elsa Maria Allegri, Anna Paola Capra, Mario Capasso, Valeria Capra, Alberto Garaventa, Mohamad Maghnie, Silvana Briuglia and Malgorzata Gabriela Wasniewska

Genes 2022, 13(4), 581; https://doi.org/10.3390/genes13040581 - 25 Mar 2022

Cited by 2 | Viewed by 4050

Abstract

Osteogenesis imperfecta/Ehlers–Danlos (OI/EDS) overlap syndrome is a recently described disorder of connective tissue, characterized by mutation of COL1A1 (17q21.33) or COL1A2 (7q21.3) genes, that are involved in α-1 and α-2 chains of type 1 collagen synthesis. The clinical spectrum of this new clinical [...] Read more.

Osteogenesis imperfecta/Ehlers–Danlos (OI/EDS) overlap syndrome is a recently described disorder of connective tissue, characterized by mutation of COL1A1 (17q21.33) or COL1A2 (7q21.3) genes, that are involved in α-1 and α-2 chains of type 1 collagen synthesis. The clinical spectrum of this new clinical entity is broad: patients could present a mixed phenotype that includes features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae, short stature) and Ehlers–Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility). We reported the case of a young Caucasian girl with severe short stature and a previous history of neuroblastoma, who displayed the compound phenotype of OI/EDS. Next generation sequencing was applied to the proband and her parent genome. Our patient presented a de novo heterozygous COL1A1 variant (c.3235G>A, p.Gly1079Ser), whose presence might be indicative of diagnosis of OI/EDS overlap syndrome. We also hypothesize that the association with the previous history of neuroblastoma could be influenced by the presence of COL1A1 mutation, whose role has been already described in the behavior and progression of some cancers. Full article

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15 pages, 2001 KiB

Open AccessArticle

Cognitive, Behavioral, and Sensory Profile of Pallister–Killian Syndrome: A Prospective Study of 22 Individuals

by Anna Fetta, Luca Soliani, Alessia Trevisan, Rosa Pugliano, Emilia Ricci, Veronica Di Pisa, Veronica Pignataro, Marida Angotti, Alessandro Rocca, Bianca Salce, Maria Margherita Mancardi, Lucio Giordano, Dario Pruna, Antonia Parmeggiani and Duccio Maria Cordelli

Genes 2022, 13(2), 356; https://doi.org/10.3390/genes13020356 - 16 Feb 2022

Cited by 5 | Viewed by 3467

Abstract

Background: Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister–Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and [...] Read more.

Background: Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister–Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables. Methods: Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales—Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory—Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2–18 years. Results: Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (p = 0.004 and p = 0.003), and self-injurious behaviors (p = 0.002 and p = 0.002). Patients with severe low vision had greater interference of stereotypies (p = 0.027), and frequency and severity of aggressive behaviors (p = 0.026; p = 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (p = 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (p = 0.019; p = 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores. Conclusions: The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols. Full article

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17 pages, 1320 KiB

Open AccessEditor’s ChoiceReview

Smith-Magenis Syndrome—Clinical Review, Biological Background and Related Disorders

by Berardo Rinaldi, Roberta Villa, Alessandra Sironi, Livia Garavelli, Palma Finelli and Maria Francesca Bedeschi

Genes 2022, 13(2), 335; https://doi.org/10.3390/genes13020335 - 11 Feb 2022

Cited by 30 | Viewed by 14152

Abstract

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), [...] Read more.

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%). RAI1 is a dosage-sensitive gene expressed in many tissues and acting as transcriptional regulator. The majority of individuals exhibit a mild-to-moderate range of intellectual disability. The behavioral phenotype includes significant sleep disturbance, stereotypes, maladaptive and self-injurious behaviors. In this review, we summarize current clinical knowledge and therapeutic approaches. We further discuss the common biological background shared with other conditions commonly retained in differential diagnosis. Full article

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15 pages, 7536 KiB

Open AccessArticle

Expanding Phenotype of Poirier–Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients

by Alessandro Orsini, Andrea Santangelo, Francesca Bravin, Alice Bonuccelli, Diego Peroni, Roberta Battini, Thomas Foiadelli, Veronica Bertini, Angelo Valetto, Michele Iacomino, Vincenzo Nigro, Anna Laura Torella, Marcello Scala, Valeria Capra, Maria Stella Vari, Anna Fetta, Veronica Di Pisa, Francesca Montanari, Roberta Epifanio, Paolo Bonanni, Roberto Giorda, Francesca Operto, Grazia Pastorino, Esra Sarigecili, Esra Sardaroglu, Cetin Okuyaz, Sevgan Bozdogan, Luciana Musante, Flavio Faletra, Caterina Zanus, Alessandro Ferretti, Federico Vigevano, Pasquale Striano and Duccio Maria Cordelli Show full author list Hide full author list

Genes 2022, 13(2), 276; https://doi.org/10.3390/genes13020276 - 30 Jan 2022

Cited by 14 | Viewed by 5048

Abstract

Background: Poirier–Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack [...] Read more.

Background: Poirier–Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. Methods: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. Results: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. Conclusion: Although it was not possible to assess a genotype–phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene. Full article

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15 pages, 3758 KiB

Open AccessFeature PaperArticle

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features

by Simonetta Rosato, Sheila Unger, Belinda Campos-Xavier, Stefano Giuseppe Caraffi, Laura Beltrami, Marzia Pollazzon, Ivan Ivanovski, Marco Castori, Maria Paola Bonasoni, Giuseppina Comitini, Peter G. J. Nikkels, Kristin Lindstrom, Christine Umandap, Andrea Superti-Furga and Livia Garavelli

Genes 2022, 13(2), 261; https://doi.org/10.3390/genes13020261 - 28 Jan 2022

Cited by 8 | Viewed by 3827

Abstract

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey [...] Read more.

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS. Full article

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10 pages, 775 KiB

Open AccessArticle

SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome

by Chiara Migliore, Anna Vendramin, Shane McKee, Paolo Prontera, Francesca Faravelli, Rani Sachdev, Patricia Dias, Martina Mascaro, Danilo Licastro and Germana Meroni

Genes 2022, 13(2), 252; https://doi.org/10.3390/genes13020252 - 28 Jan 2022

Cited by 1 | Viewed by 2618

Abstract

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo–tracheo–esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in [...] Read more.

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo–tracheo–esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of ‘SPECC1L syndrome’ to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo–tracheo–esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification. Full article

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2021

Jump to: 2024, 2023, 2022

14 pages, 5907 KiB

Open AccessArticle

Clinical and Genetic Findings in a Series of Eight Families with Arthrogryposis

by Marzia Pollazzon, Stefano Giuseppe Caraffi, Silvia Faccioli, Simonetta Rosato, Heidi Fodstad, Belinda Campos-Xavier, Emanuele Soncini, Giuseppina Comitini, Daniele Frattini, Teresa Grimaldi, Maria Marinelli, Davide Martorana, Antonio Percesepe, Silvia Sassi, Carlo Fusco, Giancarlo Gargano, Andrea Superti-Furga and Livia Garavelli

Genes 2022, 13(1), 29; https://doi.org/10.3390/genes13010029 - 23 Dec 2021

Cited by 7 | Viewed by 6504

Abstract

The term “arthrogryposis” is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult [...] Read more.

The term “arthrogryposis” is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys–Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis. Full article

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13 pages, 3009 KiB

Open AccessArticle

MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

by Alessandro Mussa, Diana Carli, Elisa Giorgio, Anna Maria Villar, Simona Cardaropoli, Caterina Carbonara, Maria Francesca Campagnoli, Paolo Galletto, Martina Palumbo, Simone Olivieri, Claudio Isella, Gregor Andelfinger, Marco Tartaglia, Giovanni Botta, Alfredo Brusco, Enzo Medico and Giovanni Battista Ferrero

Genes 2022, 13(1), 6; https://doi.org/10.3390/genes13010006 - 21 Dec 2021

Cited by 27 | Viewed by 9319

Abstract

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and [...] Read more.

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension. Full article

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14 pages, 2036 KiB

Open AccessArticle

Pendred Syndrome, or Not Pendred Syndrome? That Is the Question

by Paola Tesolin, Sofia Fiorino, Stefania Lenarduzzi, Elisa Rubinato, Elisabetta Cattaruzzi, Lydie Ammar, Veronica Castro, Eva Orzan, Claudio Granata, Daniele Dell’Orco, Anna Morgan and Giorgia Girotto

Genes 2021, 12(10), 1569; https://doi.org/10.3390/genes12101569 - 1 Oct 2021

Cited by 8 | Viewed by 4199

Abstract

Pendred syndrome (PDS) is the most common form of syndromic Hearing Loss (HL), characterized by sensorineural HL, inner ear malformations, and goiter, with or without hypothyroidism. SLC26A4 is the major gene involved, even though ~50% of the patients carry only one pathogenic mutation. [...] Read more.

Pendred syndrome (PDS) is the most common form of syndromic Hearing Loss (HL), characterized by sensorineural HL, inner ear malformations, and goiter, with or without hypothyroidism. SLC26A4 is the major gene involved, even though ~50% of the patients carry only one pathogenic mutation. This study aims to define the molecular diagnosis for a cohort of 24 suspected-PDS patients characterized by a deep radiological and audiological evaluation. Whole-Exome Sequencing (WES), the analysis of twelve variants upstream of SLC26A4, constituting the “CEVA haplotype” and Multiplex Ligation Probe Amplification (MLPA) searching for deletions/duplications in SLC26A4 gene have been carried out. In five patients (20.8%) homozygous/compound heterozygous SLC26A4 mutations, or pathogenic mutation in trans with the CEVA haplotype have been identified, while five subjects (20.8%) resulted heterozygous for a single variant. In silico protein modeling supported the pathogenicity of the detected variants, suggesting an effect on the protein stabilization/function. Interestingly, we identified a genotype-phenotype correlation among those patients carrying SLC26A4 mutations, whose audiograms presented a characteristic slope at the medium and high frequencies, providing new insights into PDS. Finally, an interesting homozygous variant in MYO5C has been identified in one patient negative to SLC26A4 gene, suggesting the identification of a new HL candidate gene. Full article

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10 pages, 905 KiB

Open AccessArticle

Expanding the Neurological Phenotype of Ring Chromosome 10 Syndrome: A Case Report and Review of the Literature

by Jacopo Pruccoli, Claudio Graziano, Chiara Locatelli, Lucia Maltoni, Hodman Ahmed Sheikh Maye and Duccio Maria Cordelli

Genes 2021, 12(10), 1513; https://doi.org/10.3390/genes12101513 - 26 Sep 2021

Cited by 1 | Viewed by 2667

Abstract

Ring chromosome 10 [r(10)] syndrome is a rare genetic condition, currently described in the medical literature in a small number of case report studies. Typical clinical features include microcephaly, short stature, facial dysmorphisms, ophthalmologic abnormalities and genitourinary malformations. We report a novel case [...] Read more.

Ring chromosome 10 [r(10)] syndrome is a rare genetic condition, currently described in the medical literature in a small number of case report studies. Typical clinical features include microcephaly, short stature, facial dysmorphisms, ophthalmologic abnormalities and genitourinary malformations. We report a novel case of r(10) syndrome and review the neurological and neuroradiological phenotypes of the previously described cases. Our patient, a 3 year old Italian girl, represents the 20th case of r(10) syndrome described to date. Intellectual disability/developmental delay (ID/DD), microcephaly, strabismus, hypotonia, stereotyped/aggressive behaviors and electroencephalographic abnormalities were identified in our patient, and in a series of previous cases. A brain MRI disclosed a complex malformation involving both the vermis and cerebellar hemispheres; in the literature, posterior cranial fossa abnormalities were documented by CT scan in another case. Two genes deleted in our case (ZMYND11 in 10p and EBF3 in 10q) are involved in autosomal dominant neurodevelopmental disorders, characterized by different expressions of brain and posterior cranial fossa abnormalities, ID/DD, hypotonia and behavioral problems. Our case expands the neurological and neuroradiological phenotype of r(10) syndrome. Although r(10) syndrome represents an extremely rare condition, with a clinical characterization limited to case reports, the recurrence of specific neurological and neuroradiological features suggests the need for specific genotype-phenotype studies. Full article

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12 pages, 1528 KiB

Open AccessArticle

Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

by Isabelle Jéru, Amira Nabil, Gehad El-Makkawy, Olivier Lascols, Corinne Vigouroux and Ebtesam Abdalla

Genes 2021, 12(10), 1508; https://doi.org/10.3390/genes12101508 - 26 Sep 2021

Cited by 8 | Viewed by 3543

Abstract

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation [...] Read more.

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations. Full article

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10 pages, 1335 KiB

Open AccessCase Report

Chronic Granulomatous Disease and Myelodysplastic Syndrome in a Patient with a Novel Mutation in CYBB

by Bárbara C. S. Reis, Daniela P. Cunha, Ana Paula S. Bueno, Flavia A. A. Carvalho, Juliana Dutra, Fabiana V. Mello, Maria Cecília Menks Ribeiro, Cristiane B. Milito, Elaine Sobral da Costa and Zilton Vasconcelos

Genes 2021, 12(10), 1476; https://doi.org/10.3390/genes12101476 - 23 Sep 2021

Cited by 3 | Viewed by 2602

Abstract

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis [...] Read more.

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis with variable risk of evolution to acute leukemias. Both disorders are rare and have distinct pathophysiologic mechanisms, with no known association. A 7-month-old boy presenting with recurrent infections and anemia at age 2 months underwent immunological, hematological and genetic investigation that culminated in the diagnosis of both CGD and MDS. Next generation sequencing was performed and identified a silent variant predicted as of Uncertain Significance, located in the splicing site at the end of exon 5 in CYBB. CYBB variants account for at least two thirds of CGD cases, but no previous descriptions of this variant were found in ClinVar or The Human Gene Mutation Database (HGMD) databases. We were able to demonstrate an exon 5 skipping on the proband’s cDNA, which strongly suggests the disruption of the NADPH oxidase complex, abrogating the formation of reactive oxygen species from neutrophils. Moreover, erythroid cell lineage could be also affected by NADPH oxidase complex damages. Further investigation is needed to evaluate the potential effect of CYBB gene alterations in hematopoiesis, as well as in MDS and CGD association. Full article

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14 pages, 1166 KiB

Open AccessArticle

CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations

by Beryl Royer-Bertrand, Katarina Cisarova, Florence Niel-Butschi, Laureane Mittaz-Crettol, Heidi Fodstad and Andrea Superti-Furga

Genes 2021, 12(9), 1427; https://doi.org/10.3390/genes12091427 - 16 Sep 2021

Cited by 30 | Viewed by 4240

Abstract

To assess the potential of detecting copy number variations (CNVs) directly from exome sequencing (ES) data in diagnostic settings, we developed a CNV-detection pipeline based on ExomeDepth software and applied it to ES data of 450 individuals. Initially, only CNVs affecting genes in [...] Read more.

To assess the potential of detecting copy number variations (CNVs) directly from exome sequencing (ES) data in diagnostic settings, we developed a CNV-detection pipeline based on ExomeDepth software and applied it to ES data of 450 individuals. Initially, only CNVs affecting genes in the requested diagnostic gene panels were scored and tested against arrayCGH results. Pathogenic CNVs were detected in 18 individuals. Most detected CNVs were larger than 400 kb (11/18), but three individuals had small CNVs impacting one or a few exons only and were thus not detectable by arrayCGH. Conversely, two pathogenic CNVs were initially missed, as they impacted genes not included in the original gene panel analysed, and a third one was missed as it was in a poorly covered region. The overall combined diagnostic rate (SNVs + CNVs) in our cohort was 36%, with wide differences between clinical domains. We conclude that (1) the ES-based CNV pipeline detects efficiently large and small pathogenic CNVs, (2) the detection of CNV relies on uniformity of sequencing and good coverage, and (3) in patients who remain unsolved by the gene panel analysis, CNV analysis should be extended to all captured genes, as diagnostically relevant CNVs may occur everywhere in the genome. Full article

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14 pages, 1424 KiB

Open AccessCase Report

A Rare Case of Brachyolmia with Amelogenesis Imperfecta Caused by a New Pathogenic Splicing Variant in LTBP3

by Elisabetta Flex, Valentina Imperatore, Giovanna Carpentieri, Alessandro Bruselles, Andrea Ciolfi, Simone Pizzi, Maria Giovanna Tedesco, Daniela Rogaia, Amedea Mencarelli, Giuseppe Di Cara, Alberto Verrotti, Stefania Troiani, Giuseppe Merla, Marco Tartaglia and Paolo Prontera

Genes 2021, 12(9), 1406; https://doi.org/10.3390/genes12091406 - 12 Sep 2021

Cited by 3 | Viewed by 2995

Abstract

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) [...] Read more.

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (LTBP3) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic LTBP3 variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous LTBP3 splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in LTBP3 are involved in its pathogenesis. Full article

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7 pages, 592 KiB

Open AccessCase Report

Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants

by Sébastien Lebon, Mathieu Quinodoz, Virginie G. Peter, Carole Gengler, Gaëlle Blanchard, Viviane Cina, Belinda Campos-Xavier, Carlo Rivolta and Andrea Superti-Furga

Genes 2021, 12(9), 1397; https://doi.org/10.3390/genes12091397 - 10 Sep 2021

Cited by 2 | Viewed by 2867

Abstract

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous [...] Read more.

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting. Full article

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8 pages, 229 KiB

Open AccessArticle

GLUT1 Deficiency Syndrome—Early Treatment Maintains Cognitive Development? (Literature Review and Case Report)

by Ivana Kolic, Jelena Radic Nisevic, Inge Vlasic Cicvaric, Ivona Butorac Ahel, Kristina Lah Tomulic, Silvije Segulja, Kristina Baraba Dekanic, Senada Serifi, Aleksandar Ovuka and Igor Prpic

Genes 2021, 12(9), 1379; https://doi.org/10.3390/genes12091379 - 31 Aug 2021

Cited by 8 | Viewed by 4442

Abstract

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood–brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and [...] Read more.

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood–brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and various paroxysmal neurological phenomena. In most cases, GLUT1DS is caused by heterozygous single-nucleotide variants (SNVs) in the SLC2A1 gene that provoke complete or severe impairment of the functionality and/or expression of GLUT1 in the brain. Despite the rarity of these diseases, GLUT1DS is of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms, especially if it is started as early as possible. We present a clinical phenotype, biochemical analysis, electroencephalographic and neuropsychological features of an 11-month-old boy with myoclonic seizures, hypogammaglobulinemia, and mildly impaired gross motor development. Using sequence analysis and deletion/duplication testing, deletion of an entire coding sequence in the SLC2A1 gene was detected. Early introduction of a modified Atkins diet maintained a seizure-free period without antiseizure medications and normal cognitive development in the follow-up period. Our report summarizes the clinical features of GLUT1 syndromes and discusses the importance of early identification and molecular confirmation of GLUT1DS as a treatable metabolic disorder. Full article

15 pages, 3104 KiB

Open AccessArticle

Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations

by Domenica I. Battaglia, Maria Luigia Gambardella, Stefania Veltri, Ilaria Contaldo, Giovanni Chillemi, Chiara Veredice, Michela Quintiliani, Chiara Leoni, Roberta Onesimo, Tommaso Verdolotti, Francesca Clementina Radio, Diego Martinelli, Marina Trivisano, Nicola Specchio, Charlotte Dravet, Marco Tartaglia and Giuseppe Zampino

Genes 2021, 12(9), 1316; https://doi.org/10.3390/genes12091316 - 26 Aug 2021

Cited by 16 | Viewed by 3537

Abstract

Objective: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim [...] Read more.

Objective: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim of our study was to define the natural history of epilepsy in this syndrome and exploring genotype–phenotype correlations. Methods: We performed an observational study, including 34 patients with molecularly confirmed diagnosis (11 males, mean age: 15.8 years). The mean follow-up period was 9.2 years. For all patients, we performed neurological examination, cognitive assessment when possible, neuroimaging, electrophysiological assessment and systematic assessment of epilepsy features. Correlation analyses were performed, taking into account gender, age of seizure onset, EEG features, degree of cognitive deficits, type of mutation, presence of non-epileptic paroxysmal events and neuroimaging features. Results: Epilepsy was documented in 64% of cases, a higher prevalence compared to previous reports. Patients were classified into three groups based on their electroclinical features, long-term outcome and response to therapy. A genotype–phenotype correlation linking the presence/severity of epilepsy to the nature of the structural/functional consequences of mutations was observed, providing a stratification based on genotype to improve the clinical management of these patients. Full article

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14 pages, 602 KiB

Open AccessArticle

A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

by Pleuntje J. van der Sluijs, Mariëlle Alders, Alexander J. M. Dingemans, Kareesma Parbhoo, Bregje W. van Bon, Jennifer C. Dempsey, Dan Doherty, Johan T. den Dunnen, Erica H. Gerkes, Ilana M. Milller, Stephanie Moortgat, Debra S. Regier, Claudia A. L. Ruivenkamp, Betsy Schmalz, Thomas Smol, Kyra E. Stuurman, Catherine Vincent-Delorme, Bert B. A. de Vries, Bekim Sadikovic, Scott E. Hickey, Jill A. Rosenfeld, Isabelle Maystadt and Gijs W. E. Santen Show full author list Hide full author list

Genes 2021, 12(8), 1275; https://doi.org/10.3390/genes12081275 - 20 Aug 2021

Cited by 8 | Viewed by 4971

Abstract

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of [...] Read more.

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses. Full article

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15 pages, 2068 KiB

Open AccessArticle

Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3

by Anna Kutkowska-Kaźmierczak, Maria Boczar, Ewa Kalka, Jennifer Castañeda, Jakub Klapecki, Aleksandra Pietrzyk, Artur Barczyk, Olga Malinowska, Aleksandra Landowska, Tomasz Gambin, Katarzyna Kowalczyk, Barbara Wiśniowiecka-Kowalnik, Marta Smyk, Mateusz Dawidziuk, Katarzyna Niepokój, Magdalena Paczkowska, Paweł Szyld, Beata Lipska-Ziętkiewicz, Krzysztof Szczałuba, Ewa Kostyk, Agata Runge, Karolina Rutkowska, Rafał Płoski, Beata Nowakowska, Jerzy Bal, Ewa Obersztyn and Monika Gos Show full author list Hide full author list

Genes 2021, 12(8), 1257; https://doi.org/10.3390/genes12081257 - 17 Aug 2021

Cited by 11 | Viewed by 9358

Abstract

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement [...] Read more.

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of −1 SDs to −2 SDs were noted in about half of the patients; only two patients presented with short stature below −3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis. Full article

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9 pages, 896 KiB

Open AccessArticle

Posterior Lissencephaly Associated with Subcortical Band Heterotopia Due to a Variation in the CEP85L Gene: A Case Report and Refining of the Phenotypic Spectrum

by Gianluca Contrò, Alessia Micalizzi, Sara Giangiobbe, Stefano Giuseppe Caraffi, Roberta Zuntini, Simonetta Rosato, Marzia Pollazzon, Alessandra Terracciano, Manuela Napoli, Susanna Rizzi, Grazia Gabriella Salerno, Francesca Clementina Radio, Marcello Niceta, Elena Parrini, Carlo Fusco, Giancarlo Gargano, Renzo Guerrini, Marco Tartaglia, Antonio Novelli, Orsetta Zuffardi and Livia Garavelli Show full author list Hide full author list

Genes 2021, 12(8), 1208; https://doi.org/10.3390/genes12081208 - 5 Aug 2021

Cited by 2 | Viewed by 4995

Abstract

Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L, encoding a protein [...] Read more.

Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo–occipito–parietal regions of both hemispheres with “double-cortex” (Dobyns’ 1–2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the CEP85L gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic CEP85L variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with CEP85L variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly. Full article

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12 pages, 2198 KiB

Open AccessCase Report

Fibrodysplasia Ossificans Progressiva: A Challenging Diagnosis

by Daniele De Brasi, Francesca Orlando, Valeria Gaeta, Maria De Liso, Fabio Acquaviva, Luigi Martemucci, Augusto Mastrominico and Maja Di Rocco

Genes 2021, 12(8), 1187; https://doi.org/10.3390/genes12081187 - 30 Jul 2021

Cited by 12 | Viewed by 5209

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics of FOP are related to dysregulated chondrogenesis, with heterotopic ossification being the most typical feature. Activating mutations of activin receptor A type I (ACVR1), [...] Read more.

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics of FOP are related to dysregulated chondrogenesis, with heterotopic ossification being the most typical feature. Activating mutations of activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the skeletal and nonskeletal features. The clinical phenotype is always consistent, with congenital bilateral hallux valgus malformation and early-onset heterotopic ossification occurring spontaneously or, more frequently, precipitated by trauma. Painful, recurrent soft-tissue swellings (flare-ups) precede localized heterotopic ossification that can occur at any location, typically affecting regions near the axial skeleton and later progressing to the appendicular bones. A diagnosis of FOP is suspected in a proband presenting with hallux valgus malformation, heterotopic ossification, and confirmed by the identification of a heterozygous pathogenic variant in the ACVR1/ALK2 gene. Avoiding unnecessary surgical procedures, prescribing prophylactic corticosteroids, preventing falls, and using protective headgear represent essential interventions for care management. Different classes of medications to contain acute inflammation flare-ups have been proposed, with high dose corticosteroids and nonsteroidal anti-inflammatory drugs usually utilized. Here, we report on two FOP patients, with typical clinical features summarizing the principal aspects of FOP, and we aim to provide comprehensive information outlining some unusual findings, possibly contributing to FOP’s definition and management. Full article

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7 pages, 606 KiB

Open AccessArticle

Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations

by Agnieszka Stembalska, Małgorzata Rydzanicz, Agnieszka Pollak, Grazyna Kostrzewa, Piotr Stawinski, Mateusz Biela, Rafal Ploski and Robert Smigiel

Genes 2021, 12(7), 1078; https://doi.org/10.3390/genes12071078 - 16 Jul 2021

Cited by 4 | Viewed by 3645

Abstract

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of [...] Read more.

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period. Full article

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13 pages, 834 KiB

Open AccessReview

Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum

by Angelo Selicorni, Milena Mariani, Antonella Lettieri and Valentina Massa

Genes 2021, 12(7), 1075; https://doi.org/10.3390/genes12071075 - 15 Jul 2021

Cited by 25 | Viewed by 13749

Abstract

Cornelia de Lange syndrome (CdLS) is a genetic disease that exemplifies the evolution of knowledge in the field of rare genetic disorders. Originally described as a unique pattern of major and minor anomalies, over time this syndrome has been shown to be characterized [...] Read more.

Cornelia de Lange syndrome (CdLS) is a genetic disease that exemplifies the evolution of knowledge in the field of rare genetic disorders. Originally described as a unique pattern of major and minor anomalies, over time this syndrome has been shown to be characterized by a significant variability of clinical expression. By increasing the number of patients described, knowledge of the natural history of the condition has been enriched with the demonstration of the relative frequency of various potential comorbidities. Since 2006, the discovery of CdLS’s molecular basis has shown an equally vast genetic heterogeneity linked to the presence of variants in genes encoding for the cohesin complex pathway. The most recent clinical-genetic data led to the classification of the “original syndrome” into a “clinical spectrum” that foresees the presence of classic patients, of non-classic forms, and of conditions that show a modest phenotypic overlapping with the original disease. Finally, the knowledge of the molecular basis of the disease has allowed the development of basic research projects that could lay the foundations for the development of possible innovative pharmacological treatments. Full article

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7 pages, 10035 KiB

Open AccessCase Report

Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia

by Olivia A. Zin, Luiza M. Neves, Fabiana L. Motta, Dafne D. G. Horovitz, Leticia Guida, Leonardo H. F. Gomes, Daniela P. Cunha, Ana Paula S. Rodrigues, Andrea A. Zin, Juliana M. F. Sallum and Zilton F. M. Vasconcelos

Genes 2021, 12(7), 1069; https://doi.org/10.3390/genes12071069 - 13 Jul 2021

Cited by 6 | Viewed by 2651

Abstract

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed [...] Read more.

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia. Full article

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19 pages, 1261 KiB

Open AccessReview

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

by Allan Bayat, Michael Bayat, Guido Rubboli and Rikke S. Møller

Genes 2021, 12(7), 1051; https://doi.org/10.3390/genes12071051 - 8 Jul 2021

Cited by 50 | Viewed by 13169

Abstract

The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and [...] Read more.

The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox–Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies. Full article

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16 pages, 638 KiB

Open AccessArticle

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

by Ilse Meerschaut, Sarah Vergult, Annelies Dheedene, Björn Menten, Katya De Groote, Hans De Wilde, Laura Muiño Mosquera, Joseph Panzer, Kristof Vandekerckhove, Paul J. Coucke, Daniël De Wolf and Bert Callewaert

Genes 2021, 12(7), 1048; https://doi.org/10.3390/genes12071048 - 8 Jul 2021

Cited by 8 | Viewed by 3352

Abstract

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain [...] Read more.

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings. Full article

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11 pages, 282 KiB

Open AccessReview

Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights

by Giulio Calcagni, Flaminia Pugnaloni, Maria Cristina Digilio, Marta Unolt, Carolina Putotto, Marcello Niceta, Anwar Baban, Francesca Piceci Sparascio, Fabrizio Drago, Alessandro De Luca, Marco Tartaglia, Bruno Marino and Paolo Versacci

Genes 2021, 12(7), 1047; https://doi.org/10.3390/genes12071047 - 8 Jul 2021

Cited by 15 | Viewed by 3313

Abstract

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by [...] Read more.

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options. Full article

33 pages, 2833 KiB

Open AccessReview

ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises

by Judith C. Birkhoff, Danny Huylebroeck and Andrea Conidi

Genes 2021, 12(7), 1037; https://doi.org/10.3390/genes12071037 - 3 Jul 2021

Cited by 20 | Viewed by 10057

Abstract

After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, [...] Read more.

After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, it was further identified as causal gene causing Mowat-Wilson Syndrome (MOWS) and novel regulator of epithelial–mesenchymal transition (EMT). ZEB2’s functions and action mechanisms in mouse embryos were first addressed in its main sites of expression, with focus on those that helped to explain neurodevelopmental and neural crest defects seen in MOWS patients. By doing so, ZEB2 was identified in the forebrain as the first TF that determined timing of neuro-/gliogenesis, and thereby also the extent of different layers of the cortex, in a cell non-autonomous fashion, i.e., by its cell-intrinsic control within neurons of neuron-to-progenitor paracrine signaling. Transcriptomics-based phenotyping of Zeb2 mutant mouse cells have identified large sets of intact-ZEB2 dependent genes, and the cKO approaches also moved to post-natal brain development and diverse other systems in adult mice, including hematopoiesis and various cell types of the immune system. These new studies start to highlight the important adult roles of ZEB2 in cell–cell communication, including after challenge, e.g., in the infarcted heart and fibrotic liver. Such studies may further evolve towards those documenting the roles of ZEB2 in cell-based repair of injured tissue and organs, downstream of actions of diverse growth factors, which recapitulate developmental signaling principles in the injured sites. Evident questions are about ZEB2’s direct target genes, its various partners, and ZEB2 as a candidate modifier gene, e.g., in other (neuro)developmental disorders, but also the accurate transcriptional and epigenetic regulation of its mRNA expression sites and levels. Other questions start to address ZEB2’s function as a niche-controlling regulatory TF of also other cell types, in part by its modulation of growth factor responses (e.g., TGFβ/BMP, Wnt, Notch). Furthermore, growing numbers of mapped missense as well as protein non-coding mutations in MOWS patients are becoming available and inspire the design of new animal model and pluripotent stem cell-based systems. This review attempts to summarize in detail, albeit without discussing ZEB2’s role in cancer, hematopoiesis, and its emerging roles in the immune system, how intense ZEB2 research has arrived at this exciting intersection. Full article

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9 pages, 533 KiB

Open AccessFeature PaperArticle

The Phenotypic Spectrum of 15q13.3 Region Duplications: Report of 5 Patients

by Magdalena Budisteanu, Sorina Mihaela Papuc, Ioana Streata, Mihai Cucu, Andrei Pirvu, Simona Serban-Sosoi, Alina Erbescu, Emanuela Andrei, Catrinel Iliescu, Doina Ioana, Emilia Severin, Mihai Ioana and Aurora Arghir

Genes 2021, 12(7), 1025; https://doi.org/10.3390/genes12071025 - 1 Jul 2021

Cited by 15 | Viewed by 4726

Abstract

Chromosome 15q13.3 microduplications are associated with a wide spectrum of clinical presentations ranging from normal to different neuropsychiatric conditions, such as developmental delay (DD), intellectual disability (ID), epilepsy, hypotonia, autism spectrum disorders (ASD), attention-deficit hyperactivity disorder, and schizophrenia. The smallest region of overlap [...] Read more.

Chromosome 15q13.3 microduplications are associated with a wide spectrum of clinical presentations ranging from normal to different neuropsychiatric conditions, such as developmental delay (DD), intellectual disability (ID), epilepsy, hypotonia, autism spectrum disorders (ASD), attention-deficit hyperactivity disorder, and schizophrenia. The smallest region of overlap for 15q13.3 duplications encompasses the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, a strong candidate for the behavioral abnormalities. We report on a series of five patients with 15q13.3 duplications detected by chromosomal microarray. The size of the duplications ranged from 378 to 537 kb, and involved the CHRNA7 gene in all patients. The most common clinical features, present in all patients, were speech delay, autistic behavior, and muscle hypotonia; DD/ID was present in three patients. One patient presented epileptic seizures; EEG anomalies were observed in three patients. No consistent dysmorphic features were noted. Neuroimaging studies revealed anomalies in two patients: Dandy–Walker malformation and a right temporal cyst. 15q13.3 duplications are associated with various neuropsychiatric features, including speech delay, hypotonia, ASD, and ID, also present in our patient group. Our study brings detailed clinical and molecular data from five ASD patients with 15q13.3 microduplications involving the CHRNA7 gene, contributing to the existing knowledge about the association of 15q13.3 duplications with neuropsychiatric phenotypes. Full article

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11 pages, 627 KiB

Open AccessArticle

Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype

by Manuela Priolo, Francesca Clementina Radio, Simone Pizzi, Letizia Pintomalli, Francesca Pantaleoni, Cecilia Mancini, Viviana Cordeddu, Emilio Africa, Corrado Mammì, Bruno Dallapiccola and Marco Tartaglia

Genes 2021, 12(7), 1009; https://doi.org/10.3390/genes12071009 - 30 Jun 2021

Cited by 6 | Viewed by 3315

Abstract

Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes [...] Read more.

Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt. Full article

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15 pages, 1690 KiB

Open AccessReview

Neurological Phenotype of Mowat-Wilson Syndrome

by Duccio Maria Cordelli, Veronica Di Pisa, Anna Fetta, Livia Garavelli, Lucia Maltoni, Luca Soliani and Emilia Ricci

Genes 2021, 12(7), 982; https://doi.org/10.3390/genes12070982 - 27 Jun 2021

Cited by 11 | Viewed by 4084

Abstract

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt [...] Read more.

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways. Full article

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14 pages, 874 KiB

Open AccessArticle

Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation

by Roberta Onesimo, Daniela Ricci, Cristiana Agazzi, Simona Leone, Maria Petrianni, Lorenzo Orazi, Filippo Amore, Annabella Salerni, Chiara Leoni, Daniela Chieffo, Marco Tartaglia, Eugenio Mercuri and Giuseppe Zampino

Genes 2021, 12(7), 972; https://doi.org/10.3390/genes12070972 - 25 Jun 2021

Cited by 11 | Viewed by 2396

Abstract

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and [...] Read more.

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype–ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype–phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do. Full article

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22 pages, 2398 KiB

Open AccessReview

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

by Julien Van Gils, Frederique Magdinier, Patricia Fergelot and Didier Lacombe

Genes 2021, 12(7), 968; https://doi.org/10.3390/genes12070968 - 24 Jun 2021

Cited by 48 | Viewed by 13125

Abstract

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP [...] Read more.

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy. Full article

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12 pages, 1722 KiB

Open AccessArticle

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples

by Francesca Peluso, Stefano Giuseppe Caraffi, Roberta Zuntini, Gabriele Trimarchi, Ivan Ivanovski, Lara Valeri, Veronica Barbieri, Maria Marinelli, Alessia Pancaldi, Nives Melli, Claudia Cesario, Emanuele Agolini, Elena Cellini, Francesca Clementina Radio, Antonella Crisafi, Manuela Napoli, Renzo Guerrini, Marco Tartaglia, Antonio Novelli, Giancarlo Gargano, Orsetta Zuffardi and Livia Garavelli Show full author list Hide full author list

Genes 2021, 12(7), 962; https://doi.org/10.3390/genes12070962 - 24 Jun 2021

Viewed by 2789

Abstract

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed [...] Read more.

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies. Full article

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13 pages, 2776 KiB

Open AccessArticle

CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report

by Magdalena Badura-Stronka, Anna Winczewska-Wiktor, Anna Pietrzak, Adam Sebastian Hirschfeld, Tomasz Zemojtel, Katarzyna Wołyńska, Katarzyna Bednarek-Rajewska, Monika Seget-Dubaniewicz, Agnieszka Matheisel, Anna Latos-Bielenska and Barbara Steinborn

Genes 2021, 12(7), 956; https://doi.org/10.3390/genes12070956 - 23 Jun 2021

Cited by 4 | Viewed by 3079

Abstract

CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype [...] Read more.

CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype associated with LINCL, except she did not present spontaneous myoclonus, her symptoms occurrence was slower and developed focal sensory visual seizures. In addition, whole-exome sequencing identified a novel homozygous variant in CLN8, c.531G>T, resulting in p.Trp177Cys. Ultrastructural examination featured abundant lipofuscin deposits within mucosal cells, macrophages, and monocytes. We report a novel CLN8 mutation as a cause for NCL8 in a girl with developmental delay and epilepsy, cerebellar syndrome, visual loss, and progressive cognitive and motor regression. This case, together with an analysis of the available literature, emphasizes the existence of a continuous spectrum of CLN8-associated phenotypes rather than a sharp distinction between them. Full article

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10 pages, 1534 KiB

Open AccessArticle

Adducted Thumb and Peripheral Polyneuropathy: Diagnostic Supports in Suspecting White–Sutton Syndrome: Case Report and Review of the Literature

by Gabriele Trimarchi, Stefano Giuseppe Caraffi, Francesca Clementina Radio, Sabina Barresi, Gianluca Contrò, Simone Pizzi, Ilenia Maini, Marzia Pollazzon, Carlo Fusco, Silvia Sassi, Davide Nicoli, Manuela Napoli, Rosario Pascarella, Giancarlo Gargano, Orsetta Zuffardi, Marco Tartaglia and Livia Garavelli

Genes 2021, 12(7), 950; https://doi.org/10.3390/genes12070950 - 22 Jun 2021

Cited by 4 | Viewed by 6509

Abstract

One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White–Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on [...] Read more.

One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White–Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb—a remarkable clinical feature in the first years of life—and heterozygous for a previously unreported, de novo splicing variant in POGZ. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition. Full article

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9 pages, 986 KiB

Open AccessArticle

Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome

by Ashley Vasko, Theodore G. Drivas and Samantha A. Schrier Vergano

Genes 2021, 12(6), 937; https://doi.org/10.3390/genes12060937 - 19 Jun 2021

Cited by 48 | Viewed by 7260

Abstract

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, [...] Read more.

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad. Full article

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9 pages, 4466 KiB

Open AccessArticle

Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype–Phenotype Correlation in Females

by Ilenia Maini, Stefano G. Caraffi, Francesca Peluso, Lara Valeri, Davide Nicoli, Steven Laurie, Chiara Baldo, Orsetta Zuffardi and Livia Garavelli

Genes 2021, 12(6), 900; https://doi.org/10.3390/genes12060900 - 10 Jun 2021

Cited by 13 | Viewed by 7920

Abstract

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of [...] Read more.

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype–phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals. Full article

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14 pages, 3028 KiB

Open AccessArticle

Pallister–Killian Syndrome versus Trisomy 12p—A Clinical Study of 5 New Cases and a Literature Review

by Aurora Arghir, Roxana Popescu, Irina Resmerita, Magdalena Budisteanu, Lacramioara Ionela Butnariu, Eusebiu Vlad Gorduza, Mihaela Gramescu, Monica Cristina Panzaru, Sorina Mihaela Papuc, Adriana Sireteanu, Andreea Tutulan-Cunita and Cristina Rusu

Genes 2021, 12(6), 811; https://doi.org/10.3390/genes12060811 - 26 May 2021

Cited by 3 | Viewed by 9863

Abstract

Pallister–Killian syndrome (PKS) is a rare, sporadic disorder defined by a characteristic dysmorphic face, pigmentary skin anomalies, intellectual disability, hypotonia, and seizures caused by 12p tetrasomy due to an extra isochromosome 12p. We present three cases of PKS and two cases of trisomy [...] Read more.

Pallister–Killian syndrome (PKS) is a rare, sporadic disorder defined by a characteristic dysmorphic face, pigmentary skin anomalies, intellectual disability, hypotonia, and seizures caused by 12p tetrasomy due to an extra isochromosome 12p. We present three cases of PKS and two cases of trisomy 12p to illustrate and discuss features rarely cited in the literature, present certain particularities that not yet been cited, and analyze the differences between entities. Moreover, we present alternative methods of diagnosis that could be easily used in daily practice. Features not yet or rarely reported in PKS literature include marked excess of hair on the forehead and ears in the first months of life, a particular eye disorder (abnormal iris color with pointed pupil), connective tissue defects, repeated episodes of infection and autonomic dysfunction, endocrine malfunction as a possible cause of postnatal growth deficit, more complex sensory impairments, and mild early myoclonic jerks. After performing different combinations of tests, we conclude that MLPA (follow-up kit P230-B1) or array CGH using DNA extracted from a buccal swab is a reliable method of diagnosis in PKS and we recommend either one as a first intention diagnostic test. In cases without major defects associated (suspicion trisomy 12p), subtelomeric MLPA should be performed first. Full article

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9 pages, 809 KiB

Open AccessCase Report

Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

by Angela Sparago, Flavia Cerrato, Laura Pignata, Francisco Cammarata-Scalisi, Livia Garavelli, Carmelo Piscopo, Alessandra Vancini and Andrea Riccio

Genes 2021, 12(5), 706; https://doi.org/10.3390/genes12050706 - 9 May 2021

Cited by 3 | Viewed by 2571

Abstract

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls [...] Read more.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C. Full article

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33 pages, 854 KiB

Open AccessReview

Kabuki Syndrome—Clinical Review with Molecular Aspects

by Snir Boniel, Krystyna Szymańska, Robert Śmigiel and Krzysztof Szczałuba

Genes 2021, 12(4), 468; https://doi.org/10.3390/genes12040468 - 25 Mar 2021

Cited by 54 | Viewed by 20113

Abstract

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large [...] Read more.

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals. Full article

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