Genes

Research

10 pages, 283 KiB

Open AccessArticle

Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation

by Carolina Sanchez-Jimeno, Fiona Blanco-Kelly, Fermina López-Grondona, Rebeca Losada-Del Pozo, Beatriz Moreno, María Rodrigo-Moreno, Elena Martinez-Cayuelas, Rosa Riveiro-Alvarez, María Fenollar-Cortés, Carmen Ayuso, Marta Rodríguez de Alba, Isabel Lorda-Sanchez and Berta Almoguera

Genes 2021, 12(9), 1360; https://doi.org/10.3390/genes12091360 - 30 Aug 2021

Cited by 19 | Viewed by 4106

Abstract

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of [...] Read more.

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

11 pages, 1128 KiB

Open AccessArticle

Clinical Phenotypic Spectrum of 4095 Individuals with Down Syndrome from Text Mining of Electronic Health Records

by James Margolin Havrilla, Mengge Zhao, Cong Liu, Chunhua Weng, Ingo Helbig, Elizabeth Bhoj and Kai Wang

Genes 2021, 12(8), 1159; https://doi.org/10.3390/genes12081159 - 28 Jul 2021

Cited by 7 | Viewed by 2425

Abstract

Human genetic disorders, such as Down syndrome, have a wide variety of clinical phenotypic presentations, and characterizing each nuanced phenotype and subtype can be difficult. In this study, we examined the electronic health records of 4095 individuals with Down syndrome at the Children’s [...] Read more.

Human genetic disorders, such as Down syndrome, have a wide variety of clinical phenotypic presentations, and characterizing each nuanced phenotype and subtype can be difficult. In this study, we examined the electronic health records of 4095 individuals with Down syndrome at the Children’s Hospital of Philadelphia to create a method to characterize the phenotypic spectrum digitally. We extracted Human Phenotype Ontology (HPO) terms from quality-filtered patient notes using a natural language processing (NLP) approach MetaMap. We catalogued the most common HPO terms related to Down syndrome patients and compared the terms with those from a baseline population. We characterized the top 100 HPO terms by their frequencies at different ages of clinical visits and highlighted selected terms that have time-dependent distributions. We also discovered phenotypic terms that have not been significantly associated with Down syndrome, such as “Proptosis”, “Downslanted palpebral fissures”, and “Microtia”. In summary, our study demonstrated that the clinical phenotypic spectrum of individual with Mendelian diseases can be characterized through NLP-based digital phenotyping on population-scale electronic health records (EHRs). Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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17 pages, 5163 KiB

Open AccessArticle

DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome

by Oxana Yu. Naumova, Rebecca Lipschutz, Sergey Yu. Rychkov, Olga V. Zhukova and Elena L. Grigorenko

Genes 2021, 12(8), 1115; https://doi.org/10.3390/genes12081115 - 23 Jul 2021

Cited by 6 | Viewed by 2189

Abstract

Recent research has provided evidence on genome-wide alterations in DNA methylation patterns due to trisomy 21, which have been detected in various tissues of individuals with Down syndrome (DS) across different developmental stages. Here, we report new data on the systematic genome-wide DNA [...] Read more.

Recent research has provided evidence on genome-wide alterations in DNA methylation patterns due to trisomy 21, which have been detected in various tissues of individuals with Down syndrome (DS) across different developmental stages. Here, we report new data on the systematic genome-wide DNA methylation perturbations in blood cells of individuals with DS from a previously understudied age group—young children. We show that the study findings are highly consistent with those from the prior literature. In addition, utilizing relevant published data from two other developmental stages, neonatal and adult, we track a quasi-longitudinal trend in the DS-associated DNA methylation patterns as a systematic epigenomic destabilization with age. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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17 pages, 3177 KiB

Open AccessArticle

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

by Ilaria Catusi, Maria Garzo, Anna Paola Capra, Silvana Briuglia, Chiara Baldo, Maria Paola Canevini, Rachele Cantone, Flaviana Elia, Francesca Forzano, Ornella Galesi, Enrico Grosso, Michela Malacarne, Angela Peron, Corrado Romano, Monica Saccani, Lidia Larizza and Maria Paola Recalcati

Genes 2021, 12(5), 652; https://doi.org/10.3390/genes12050652 - 27 Apr 2021

Cited by 11 | Viewed by 4195

Abstract

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of [...] Read more.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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15 pages, 25505 KiB

Open AccessArticle

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications

by Thiago Corrêa, Cíntia B. Santos-Rebouças, Maytza Mayndra, Albert Schinzel and Mariluce Riegel

Genes 2021, 12(5), 632; https://doi.org/10.3390/genes12050632 - 23 Apr 2021

Viewed by 2873

Abstract

Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How [...] Read more.

Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How different contiguous genes from a duplicated genomic region interact and dynamically affect the expression of each other remains unclear in most cases. Here, we report a genomic comparative delineation of genes located in duplicated chromosomal regions 8q24.13q24.3, 18p11.32p11.21, and Xq22.3q27.2 in three patients followed up at our genetics service who has the intellectual disability (ID) as a common phenotype. We integrated several genomic data levels by identification of gene content within the duplications, protein-protein interactions, and functional analysis on specific tissues. We found functional relationships among genes from three different duplicated chromosomal regions, reflecting interactions of protein-coding genes and their involvement in common cellular subnetworks. Furthermore, the sharing of common significant biological processes associated with ID has been demonstrated between proteins from the different chromosomal regions. Finally, we elaborated a shared model of pathways directly or indirectly related to the central nervous system (CNS), which could perturb cognitive function and lead to ID in the three duplication conditions. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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Review

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15 pages, 572 KiB

Open AccessReview

Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency

by Luigia Rossi, Francesca Nardecchia, Francesca Pierigè, Rossella Ventura, Claudia Carducci, Vincenzo Leuzzi, Mauro Magnani, Simona Cabib and Tiziana Pascucci

Genes 2021, 12(8), 1201; https://doi.org/10.3390/genes12081201 - 2 Aug 2021

Cited by 4 | Viewed by 3204

Abstract

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental [...] Read more.

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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21 pages, 2612 KiB

Open AccessReview

Rett Syndrome Spectrum in Monogenic Developmental-Epileptic Encephalopathies and Epilepsies: A Review

by Carlotta Spagnoli, Carlo Fusco and Francesco Pisani

Genes 2021, 12(8), 1157; https://doi.org/10.3390/genes12081157 - 28 Jul 2021

Cited by 15 | Viewed by 3609

Abstract

Introduction: Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the Rett syndrome spectrum (RSS). Our awareness of the considerable overlap with pediatric-onset epilepsies and epileptic/developmental encephalopathies (EE/DE) genes is also growing, [...] Read more.

Introduction: Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the Rett syndrome spectrum (RSS). Our awareness of the considerable overlap with pediatric-onset epilepsies and epileptic/developmental encephalopathies (EE/DE) genes is also growing, and the presence of variable clinical features inside a general frame of commonalities has drawn renewed attention into deep phenotyping. Methods: We decided to review the medical literature on atypical Rett syndrome and “Rett-like” phenotypes, with special emphasis on described cases with pediatric-onset epilepsies and/or EE-DE, evaluating Neul’s criteria for Rett syndrome and associated movement disorders and notable stereotypies. Results: “Rett-like” features were described in syndromic and non-syndromic monogenic epilepsy- and DE/EE-related genes, in “intellectual disability plus epilepsy”-related genes and in neurodegenerative disorders. Additionally, prominent stereotypies can be observed in monogenic complex neurodevelopmental disorders featuring epilepsy with or without autistic features outside of the RSS. Conclusions: Patients share a complex neurodevelopmental and neurological phenotype (developmental delay, movement disorder) with impaired gait, abnormal tone and hand stereotypies. However, the presence and characteristics of regression and loss of language and functional hand use can differ. Finally, the frequency of additional supportive criteria and their distribution also vary widely. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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12 pages, 567 KiB

Open AccessReview

The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders

by Orly Weissberg and Evan Elliott

Genes 2021, 12(8), 1133; https://doi.org/10.3390/genes12081133 - 26 Jul 2021

Cited by 24 | Viewed by 6402

Abstract

Chromodomain-helicase-DNA-binding protein 8 (CHD8) has been identified as one of the genes with the strongest association with autism. The CHD8 protein is a transcriptional regulator that is expressed in nearly all cell types and has been implicated in multiple cellular processes, including cell [...] Read more.

Chromodomain-helicase-DNA-binding protein 8 (CHD8) has been identified as one of the genes with the strongest association with autism. The CHD8 protein is a transcriptional regulator that is expressed in nearly all cell types and has been implicated in multiple cellular processes, including cell cycle, cell adhesion, neuronal development, myelination, and synaptogenesis. Considering the central role of CHD8 in the genetics of autism, a deeper understanding of the physiological functions of CHD8 is important to understand the development of the autism phenotype and potential therapeutic targets. Different CHD8 mutant mouse models were developed to determine autism-like phenotypes and to fully understand their mechanisms. Here, we review the current knowledge on CHD8, with an emphasis on mechanistic lessons gained from animal models that have been studied. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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10 pages, 1193 KiB

Open AccessReview

Genotype–Phenotype Correlations in Angelman Syndrome

by Lili Yang, Xiaoli Shu, Shujiong Mao, Yi Wang, Xiaonan Du and Chaochun Zou

Genes 2021, 12(7), 987; https://doi.org/10.3390/genes12070987 - 28 Jun 2021

Cited by 22 | Viewed by 7897

Abstract

Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack [...] Read more.

Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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16 pages, 2461 KiB

Open AccessReview

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

by Stijn R. van de Plassche and Arjan P. M. de Brouwer

Genes 2021, 12(5), 663; https://doi.org/10.3390/genes12050663 - 28 Apr 2021

Cited by 14 | Viewed by 6928

Abstract

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de [...] Read more.

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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9 pages, 889 KiB

Open AccessCase Report

MED12 Mutation in Two Families with X-Linked Ohdo Syndrome

by Luca Rocchetti, Eloisa Evangelista, Luigia De Falco, Giovanni Savarese, Pasquale Savarese, Raffaella Ruggiero, Luigi D’Amore, Alberto Sensi and Antonio Fico

Genes 2021, 12(9), 1328; https://doi.org/10.3390/genes12091328 - 27 Aug 2021

Cited by 4 | Viewed by 2875

Abstract

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been [...] Read more.

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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7 pages, 915 KiB

Open AccessCase Report

Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

by Ester Di Muro, Pietro Palumbo, Mario Benvenuto, Maria Accadia, Marilena Carmela Di Giacomo, Sergio Manieri, Rosaria Abate, Maria Tagliente, Stefano Castellana, Tommaso Mazza, Massimo Carella and Orazio Palumbo

Genes 2021, 12(8), 1116; https://doi.org/10.3390/genes12081116 - 23 Jul 2021

Cited by 5 | Viewed by 3051

Abstract

The cohesin complex is a large evolutionary conserved functional unit which plays an essential role in DNA repair and replication, chromosome segregation and gene expression. It consists of four core proteins, SMC1A, SMC3, RAD21, and STAG1/2, and by proteins regulating the interaction between [...] Read more.

The cohesin complex is a large evolutionary conserved functional unit which plays an essential role in DNA repair and replication, chromosome segregation and gene expression. It consists of four core proteins, SMC1A, SMC3, RAD21, and STAG1/2, and by proteins regulating the interaction between the complex and the chromosomes. Mutations in the genes coding for these proteins have been demonstrated to cause multisystem developmental disorders known as “cohesinopathies”. The most frequent and well recognized among these distinctive clinical conditions are the Cornelia de Lange syndrome (CdLS, OMIM 122470) and Roberts syndrome (OMIM 268300). STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. Pathogenic variants in STAG1 gene have recently been reported to cause an emerging syndromic form of neurodevelopmental disorder that is to date poorly characterized. Here, we describe a 5 year old female patient with neurodevelopmental delay, mild intellectual disability, dysmorphic features and congenital anomalies, in which next generation sequencing analysis allowed us to identify a novel pathogenic variation c.2769_2770del p.(Ile924Serfs*8) in STAG1 gene, which result to be de novo. The variant has never been reported before in medical literature and is absent in public databases. Thus, it is useful to expand the molecular spectrum of clinically relevant alterations of STAG1 and their phenotypic consequences. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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8 pages, 1223 KiB

Open AccessCase Report

Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene

by Babylakshmi Muthusamy, Anikha Bellad, Satish Chandra Girimaji and Akhilesh Pandey

Genes 2021, 12(3), 452; https://doi.org/10.3390/genes12030452 - 22 Mar 2021

Cited by 6 | Viewed by 4704

Abstract

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 [...] Read more.

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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10 pages, 1086 KiB

Open AccessCase Report

Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies

by Pietro Palumbo, Ester Di Muro, Maria Accadia, Mario Benvenuto, Marilena Carmela Di Giacomo, Stefano Castellana, Tommaso Mazza, Marco Castori, Orazio Palumbo and Massimo Carella

Genes 2021, 12(2), 229; https://doi.org/10.3390/genes12020229 - 5 Feb 2021

Cited by 8 | Viewed by 3447

Abstract

Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting [...] Read more.

Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated. Full article

(This article belongs to the Special Issue Genetics and Genomics of Intellectual Disability)

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