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Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances
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Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 2185

Special Issue Editors

Dr. Judit Bene

E-Mail Website
Guest Editor
Department of Medical Genetics, Medical School, Clinical Center, University of Pécs, 7624 Pécs, Hungary
Interests: molecular genetics and genomics; next generation sequencing; rare diseases; genetic testing; neurocutaneous syndromes; copy number variations
Special Issues, Collections and Topics in MDPI journals
Dr. Kinga Hadzsiev

E-Mail Website
Guest Editor
Department of Medical Genetics, Medical School, University of Pécs, 7624 Pécs, Hungary
Interests: autism spectrum disorders; genomic disorders; epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare diseases, defined as life-threatening, chronically debilitating conditions, represent a substantial public health burden as they affect ca. 2–6% of the population. Currently, there are around 5000–8000 different rare diseases, and these numbers are continuing to increase. Despite intensive research, the genetic etiology and pathomechanisms of the majority of rare diseases are still unclear, and most of them do not yet have an approved therapy. Their diagnostics and care pathways are also challenging due to their rarity, heterogeneous manifestations, multisystem involvement and the often-observed incomplete penetrance. In addition, patients with undiagnosed genetic diseases often face a diagnostic odyssey that lasts for an average of eight years; moreover, a certain number of patients receive a misdiagnosis.

However, due to new sophisticated technologies, such as high-throughput sequencing and mass spectrometry, an increasing number of genomic and metabolomic data for various rare disorders have recently become available. These data could help us to understand biological mechanisms, identify new genes, determine causative mutations, discover biomarkers and ultimately develop novel therapeutics and diagnostics methods.

The aim of this Special Issue is to collect original and review articles that provide cutting-edge knowledge related to genetic, genomic and metabolomic investigations in rare disorders.

Dr. Judit Bene
Dr. Kinga Hadzsiev
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare diseases
  • genotype–phenotype analyses
  • NGS
  • mass spectrometry
  • biomarker discovery
  • molecular targeted therapy

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Published Papers (3 papers)

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Research

32 pages, 1265 KiB  
Article
Concordance Between Biochemical and Molecular Diagnosis Obtained by WES in Mexican Patients with Inborn Errors of Intermediary Metabolism: Utility for Therapeutic Management
by Marcela Vela-Amieva, Miguel Angel Alcántara-Ortigoza, Ariadna González-del Angel, Liliana Fernández-Hernández, Miriam Erandi Reyna-Fabián, Bernardette Estandía-Ortega, Sara Guillén-López, Lizbeth López-Mejía, Leticia Belmont-Martínez, Rosa Itzel Carrillo-Nieto, Isabel Ibarra-González, Seung-Woo Ryu, Hane Lee and Cynthia Fernández-Lainez
Int. J. Mol. Sci. 2024, 25(21), 11722; https://doi.org/10.3390/ijms252111722 - 31 Oct 2024
Viewed by 774
Abstract
Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the [...] Read more.
Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)
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13 pages, 4911 KiB  
Article
Molecular and Clinical Heterogeneity in Hungarian Patients with Treacher Collins Syndrome—Identification of Two Novel Mutations by Next-Generation Sequencing
by Gréta Antal, Anna Zsigmond, Ágnes Till, András Szabó, Anita Maász, Judit Bene and Kinga Hadzsiev
Int. J. Mol. Sci. 2024, 25(21), 11400; https://doi.org/10.3390/ijms252111400 - 23 Oct 2024
Viewed by 430
Abstract
Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder with variable penetrance and high genetic and phenotypic heterogeneity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, and POLR1B genes, and its major characteristic features are malar and [...] Read more.
Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder with variable penetrance and high genetic and phenotypic heterogeneity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, and POLR1B genes, and its major characteristic features are malar and mandibular hypoplasia, downward slanting of the palpebral fissures, and conductive hearing loss. In this study, five patients (two males and three females, age range from 2 to 29 years) with TCS were tested by Next-Generation Sequencing (NGS)-based sequencing and clinically characterized. Genetic analyses detected two deletions and one insertion in the TCOF1 gene and one missense variant in the POLR1D gene. Two novel mutations, c.1371_1372insT (p.Lys458*) in the TCOF1 gene and c.295 G>C (p.Gly99Arg) in the POLR1D gene, were identified. Moreover, two already known mutations, c.4369_4373del (p.Lys1457Glufs*12) and c.2103_2106del (p.Ser701Argfs*9) in the TCOF1 gene, were detected. The novel TCOF1 c.1371_1372insT mutation was associated with mild craniofacial manifestations and very rare symptoms of TCS, i.e., developmental delay and moderate intellectual disability. Although incomplete penetrance is a known phenomenon in TCS, surprisingly, the majority of our patients inherited the disease-causing variants from an asymptomatic mother. The unique feature of our study is the observation of causative mutation transmission between asymptomatic family members. Our results expanded the clinical and mutational spectrum of TCS and further confirmed the inter- and intra-familial variability of this disorder. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)
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12 pages, 5061 KiB  
Communication
A De Novo Splicing Mutation of STXBP1 in Epileptic Encephalopathy Associated with Hypomyelinating Leukodystrophy
by Zixuan Wang, Jun Zhang, Yunfei Zhou, Guicen Liu, Zixin Tian and Xi Song
Int. J. Mol. Sci. 2024, 25(20), 10983; https://doi.org/10.3390/ijms252010983 - 12 Oct 2024
Viewed by 626
Abstract
Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy [...] Read more.
Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy (STXBP1-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into STXBP1-E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the STXBP1 splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of STXBP1. The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in STXBP1-E. These findings strongly indicated that the haploinsufficiency of STXBP1 could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies. Full article
(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)
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