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Molecular and Genetic Diagnosis of Rare Diseases
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Molecular and Genetic Diagnosis of Rare Diseases

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

Deadline for manuscript submissions: closed (20 February 2024) | Viewed by 6269

Special Issue Editors

Dr. Martina Witsch-Baumgartner

E-Mail Website
Guest Editor
Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
Interests: the molecular diagnosis of inherited diseases; inherited metabolic diseases; genetic variant interpretation; the quality of molecular diagnosis
Dr. Beatrix Mühlegger

E-Mail Website
Guest Editor
Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
Interests: the molecular diagnosis of inherited diseases; the implementation of new technologies

Special Issue Information

Dear Colleagues,

It is estimated that rare diseases affect 1 in 10 people and that 80% of them have a genetic background (1). On average, it takes nearly 5 years for patients to receive an accurate diagnosis. Currently, over 6,500 rare diseases with a known molecular pathogenesis are described in OMIM (2). However, only about 1/3 of patients receive a diagnosis by using various methods, such as the sequencing of gene panels, microarrays, and exome sequencing.

An accurate diagnosis of rare diseases is essential in order to improve patient outcomes, provide access to specialized care and support, and increase quality of life (e.g., familial hypercholesterolemia or syndromic epilepsies). An understanding of the genetic and molecular basis of rare diseases helps to identify new therapeutic targets and develop novel treatments that not only patients with rare diseases can benefit from, but also those with more common conditions.

This Special Issue will first provide a comprehensive overview of the current state of knowledge and research in this field. Second, it will demonstrate the progress in technologies that are essential to studying the genetic background and pathomechanisms of rare diseases. Third, it will present examples of successful new diagnostic strategies for specific rare diseases and provide new clinical guidelines. Finally, this Special Issue will also be a platform for scholars to discuss emerging challenges and future prospects associated with the diagnosis of rare diseases.

Dr. Martina Witsch-Baumgartner
Dr. Beatrix Mühlegger
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. 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

  • rare disease
  • molecular diagnosis
  • OMIM
  • exome sequencing
  • microarrays
  • genome sequencing

Published Papers (6 papers)

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13 pages, 1766 KiB  
Article
Lessons Learned from Translating Genome Sequencing to Clinical Routine: Understanding the Accuracy of a Diagnostic Pipeline
by Joohyun Park, Marc Sturm, Olga Seibel-Kelemen, Stephan Ossowski and Tobias B. Haack
Genes 2024, 15(1), 136; https://doi.org/10.3390/genes15010136 - 22 Jan 2024
Viewed by 905
Abstract
The potential of genome sequencing (GS), which allows detection of almost all types of genetic variation across nearly the entire genome of an individual, greatly expands the possibility for diagnosing genetic disorders. The opportunities provided with this single test are enticing to researchers [...] Read more.
The potential of genome sequencing (GS), which allows detection of almost all types of genetic variation across nearly the entire genome of an individual, greatly expands the possibility for diagnosing genetic disorders. The opportunities provided with this single test are enticing to researchers and clinicians worldwide for human genetic research as well as clinical application. Multiple studies have highlighted the advantages of GS for genetic variant discovery, emphasizing its added value for routine clinical use. We have implemented GS as first-line genetic testing for patients with rare diseases. Here, we report on our experiences in establishing GS as a reliable diagnostic method for almost all types of genetic disorders, from validating diagnostic accuracy of sequencing pipelines to clinical implementation in routine practice. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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11 pages, 456 KiB  
Article
The Role of Next-Generation Sequencing in the Management of Patients with Suspected Non-Ischemic Cardiomyopathy after Syncope or Termination of Sudden Arrhythmic Death
by Damijan Vokač, Špela Stangler Herodež, Danijela Krgović and Nadja Kokalj Vokač
Genes 2024, 15(1), 72; https://doi.org/10.3390/genes15010072 - 05 Jan 2024
Viewed by 1069
Abstract
Cardiac arrhythmias and sudden death are frequent in patients with non-ischemic cardiomyopathy and can precede heart failure or additional symptoms where malignant cardiac arrhythmias are mostly the consequence of advanced cardiomyopathy and heart failure. Finding these subgroups and making an early diagnosis could [...] Read more.
Cardiac arrhythmias and sudden death are frequent in patients with non-ischemic cardiomyopathy and can precede heart failure or additional symptoms where malignant cardiac arrhythmias are mostly the consequence of advanced cardiomyopathy and heart failure. Finding these subgroups and making an early diagnosis could be lifesaving. In our retrospective study, we are presenting arrhythmic types of frequent cardiomyopathies where an arrhythmogenic substrate is less well defined, as in ischemic or structural heart disease. In the period of 2 years, next-generation sequencing (NGS) tests along with standard clinical tests were performed in 208 patients (67 women and 141 men; mean age, 51.2 ± 19.4 years) without ischemic or an overt structural heart disease after syncope or aborted sudden cardiac death. Genetic variants were detected in 34.4% of the study population, with a significant proportion of pathogenic variants (P) (14.4%) and variants of unknown significance (VUS) (20%). Regardless of genotype, all patients were stratified according to clinical guidelines for aggressive treatment of sudden cardiac death with an implantable cardioverter defibrillator (ICD). The P variant identified by NGS serves for an accurate diagnosis and, thus, better prevention and specific treatment of patients and their relatives. Results in our study suggest that targeted sequencing of genes associated with cardiovascular disease is an important addendum for final diagnosis, allowing the identification of a molecular genetic cause in a vast proportion of patients for a definitive diagnosis and a more specific way of treatment. VUS in this target population poses a high risk and should be considered possibly pathogenic in reanalysis. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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14 pages, 2305 KiB  
Article
Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease
by Alba Escalera-Balsera, Alberto M. Parra-Perez, Alvaro Gallego-Martinez, Lidia Frejo, Juan Martin-Lagos, Victoria Rivero de Jesus, Paz Pérez-Vázquez, Patricia Perez-Carpena and Jose A. Lopez-Escamez
Genes 2024, 15(1), 22; https://doi.org/10.3390/genes15010022 - 22 Dec 2023
Cited by 1 | Viewed by 963
Abstract
Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare [...] Read more.
Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score > 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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17 pages, 2650 KiB  
Article
Compilation of Genotype and Phenotype Data in GCDH-LOVD for Variant Classification and Further Application
by Alexandra Tibelius, Christina Evers, Sabrina Oeser, Isabelle Rinke, Anna Jauch and Katrin Hinderhofer
Genes 2023, 14(12), 2218; https://doi.org/10.3390/genes14122218 - 14 Dec 2023
Viewed by 1123
Abstract
Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological [...] Read more.
Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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11 pages, 6171 KiB  
Technical Note
Enhancing Variant Prioritization in VarFish through On-Premise Computational Facial Analysis
by Meghna Ahuja Bhasin, Alexej Knaus, Pietro Incardona, Alexander Schmid, Manuel Holtgrewe, Miriam Elbracht, Peter M. Krawitz and Tzung-Chien Hsieh
Genes 2024, 15(3), 370; https://doi.org/10.3390/genes15030370 - 17 Mar 2024
Viewed by 757
Abstract
Genomic variant prioritization is crucial for identifying disease-associated genetic variations. Integrating facial and clinical feature analyses into this process enhances performance. This study demonstrates the integration of facial analysis (GestaltMatcher) and Human Phenotype Ontology analysis (CADA) within VarFish, an open-source variant analysis framework. [...] Read more.
Genomic variant prioritization is crucial for identifying disease-associated genetic variations. Integrating facial and clinical feature analyses into this process enhances performance. This study demonstrates the integration of facial analysis (GestaltMatcher) and Human Phenotype Ontology analysis (CADA) within VarFish, an open-source variant analysis framework. Challenges related to non-open-source components were addressed by providing an open-source version of GestaltMatcher, facilitating on-premise facial analysis to address data privacy concerns. Performance evaluation on 163 patients recruited from a German multi-center study of rare diseases showed PEDIA’s superior accuracy in variant prioritization compared to individual scores. This study highlights the importance of further benchmarking and future integration of advanced facial analysis approaches aligned with ACMG guidelines to enhance variant classification. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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10 pages, 2519 KiB  
Case Report
Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report
by Zangbéwendé Guy Ouedraogo, Caroline Janel, Alexandre Janin, Gilles Millat, Sarah Langlais, Bénédicte Pontier, Marie Biard, Mathis Lepage, Christine Francannet, Fanny Laffargue and Isabelle Creveaux
Genes 2024, 15(2), 225; https://doi.org/10.3390/genes15020225 - 10 Feb 2024
Viewed by 826
Abstract
Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children’s growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in [...] Read more.
Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children’s growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5′ segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3’s function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis of Rare Diseases)
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