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Identification of Genes in Rare Syndromes
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Identification of Genes in Rare Syndromes

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 October 2023) | Viewed by 7343

Special Issue Editor

Dr. Dagmar Wieczorek

E-Mail Website
Guest Editor
Institute of Human Genetics, University Hospital and Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
Interests: syndrome; gene; signaling pathway; next generation sequencing

Special Issue Information

Dear Colleagues,

Rare diseases have attracted increasing attention in recent years. To date, about 60,000 different rare diseases—defined as a condition with an incidence lower than 5/10,000—are known, but it is generally acknowledged that many more likely exist. Within the European Union, about 30 million individuals suffer from a rare disease.

Rare diseases are complex and variable, have a chronic cause, and display health problems and/or reduced life expectancy. In most individuals, clinical findings are present from childhood. About 80% of rare diseases have a genetic basis, and most of them are not curable.

Although the molecular genetic basis is known for most rare diseases, there are many which are genetically unresolved. This Special Issue invites papers dealing with the identification of new genes in rare diseases and with new phenotypes for known genes and widening the phenotype and/or genotype for known rare diseases. We look forward to your submission.

Dr. Dagmar Wieczorek
Guest Editor

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. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • syndrome
  • gene
  • signaling pathway
  • next-generation sequencing

Published Papers (4 papers)

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Research

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13 pages, 1671 KiB  
Article
Approach to Cohort-Wide Re-Analysis of Exome Data in 1000 Individuals with Neurodevelopmental Disorders
by Insa Halfmeyer, Tobias Bartolomaeus, Bernt Popp, Maximilian Radtke, Tobias Helms, Julia Hentschel, Denny Popp and Rami Abou Jamra
Genes 2023, 14(1), 30; https://doi.org/10.3390/genes14010030 - 22 Dec 2022
Cited by 2 | Viewed by 2331
Abstract
The re-analysis of nondiagnostic exome sequencing (ES) has the potential to increase diagnostic yields in individuals with rare diseases, but its implementation in the daily routines of laboratories is limited due to restricted capacities. Here, we describe a systematic approach to re-analyse the [...] Read more.
The re-analysis of nondiagnostic exome sequencing (ES) has the potential to increase diagnostic yields in individuals with rare diseases, but its implementation in the daily routines of laboratories is limited due to restricted capacities. Here, we describe a systematic approach to re-analyse the ES data of a cohort consisting of 1040 diagnostic and nondiagnostic samples. We applied a strict filter cascade to reveal the most promising single-nucleotide variants (SNVs) of the whole cohort, which led to an average of 0.77 variants per individual that had to be manually evaluated. This variant set revealed seven novel diagnoses (0.8% of all nondiagnostic cases) and two secondary findings. Thirteen additional variants were identified by a scientific approach prior to this re-analysis and were also present in this variant set. This resulted in a total increase in the diagnostic yield of 2.3%. The filter cascade was optimised during the course of the study and finally resulted in sensitivity of 85%. After applying the filter cascade, our re-analysis took 20 h and enabled a workflow that can be used repeatedly. This work is intended to provide a practical recommendation for other laboratories wishing to introduce a resource-efficient re-analysis strategy into their clinical routine. Full article
(This article belongs to the Special Issue Identification of Genes in Rare Syndromes)
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16 pages, 1710 KiB  
Article
Routine Diagnostics Confirm Novel Neurodevelopmental Disorders
by Robin-Tobias Jauss, Sophia Schließke and Rami Abou Jamra
Genes 2022, 13(12), 2305; https://doi.org/10.3390/genes13122305 - 07 Dec 2022
Cited by 3 | Viewed by 1961
Abstract
Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM [...] Read more.
Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM entries or comprise only a small number of publicly available variants from one or a few studies. Here, we present 89 individuals harbouring variants in 77 genes for which only a small amount of public evidence on their clinical significance is available but which we still found to be relevant enough to be reported in routine diagnostics. For 21 genes, we present case reports that confirm the lack or provisionality of OMIM associations (ATP6V0A1, CNTN2, GABRD, NCKAP1, RHEB, TCF7L2), broaden the phenotypic spectrum (CC2D1A, KCTD17, YAP1) or substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142). Routine diagnostics can provide valuable information on disease associations and support for genes without requiring tremendous research efforts. Thus, our results validate and delineate gene–disorder associations with the aim of motivating clinicians and scientists in diagnostic departments to provide additional evidence via publicly available databases or by publishing short case reports. Full article
(This article belongs to the Special Issue Identification of Genes in Rare Syndromes)
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12 pages, 8731 KiB  
Case Report
FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family
by Ariane Schmetz, Jörg Schaper, Simon Thelen, Majeed Rana, Thomas Klenzner, Katharina Schaumann, Jasmin Beygo, Harald Surowy, Hermann-Josef Lüdecke and Dagmar Wieczorek
Genes 2023, 14(3), 724; https://doi.org/10.3390/genes14030724 - 15 Mar 2023
Cited by 1 | Viewed by 1129
Abstract
Multiple synostoses syndrome (OMIM: #186500, #610017, #612961, #617898) is a genetically heterogeneous group of autosomal dominant diseases characterized by abnormal bone unions. The joint fusions frequently involve the hands, feet, elbows or vertebrae. Pathogenic variants in FGF9 have been associated with multiple synostoses [...] Read more.
Multiple synostoses syndrome (OMIM: #186500, #610017, #612961, #617898) is a genetically heterogeneous group of autosomal dominant diseases characterized by abnormal bone unions. The joint fusions frequently involve the hands, feet, elbows or vertebrae. Pathogenic variants in FGF9 have been associated with multiple synostoses syndrome type 3 (SYNS3). So far, only five different missense variants in FGF9 that cause SYNS3 have been reported in 18 affected individuals. Unlike other multiple synostoses syndromes, conductive hearing loss has not been reported in SYNS3. In this report, we describe the clinical and selected radiological findings in a large multigenerational family with a novel missense variant in FGF9: c.430T>C, p.(Trp144Arg). We extend the phenotypic spectrum of SYNS3 by suggesting that cleft palate and conductive hearing loss are part of the syndrome and highlight the high degree of intrafamilial phenotypic variability. These findings should be considered when counseling affected individuals. Full article
(This article belongs to the Special Issue Identification of Genes in Rare Syndromes)
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7 pages, 2547 KiB  
Brief Report
Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy
by K. Eggermann, R. Meyer, M. Begemann, D. Dey, E. Bültmann, I. Kurth, G. C. Korenke and C. Knopp
Genes 2022, 13(12), 2356; https://doi.org/10.3390/genes13122356 - 14 Dec 2022
Cited by 2 | Viewed by 1268
Abstract
Background: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. Methods: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old [...] Read more.
Background: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. Methods: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. Results: Combined analysis of the mother’s and daughter’s duo-exome data and analysis of the mother’s and her parents’ trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. Conclusion: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult. Full article
(This article belongs to the Special Issue Identification of Genes in Rare Syndromes)
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