Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants
| Autor: | Lisbeth Silva, Sandra Alves, Maria Francisca Coutinho, Laura Vilarinho, Helena de Souza Santos, Teresa Campos, Souad Ouesleti, Maria Teresa Cardoso, Esmeralda Martins, Diogo Ribeiro, Marisa Encarnação |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
GM2A gene 030105 genetics & heredity Gangliosidosis Global Health lcsh:Chemistry molecular genetic testing (MGT) Medicine next-generation sequencing (NGS) lcsh:QH301-705.5 Spectroscopy biology High-Throughput Nucleotide Sequencing General Medicine CLN7 Phenotype Computer Science Applications Identification (biology) Doenças Lisossomais de Sobrecarga Genetic Markers Next-generation Sequencing bioinformatics analysis Genómica In silico Molecular Genetic Testing Computational biology Catalysis DNA sequencing Article Inorganic Chemistry 03 medical and health sciences Lysosomal Storage Disorders Humans Genetic Predisposition to Disease Genetic Testing Physical and Theoretical Chemistry GM2A Molecular Biology Heterogeneous group business.industry Organic Chemistry Genetic Variation GM2 Gangliosidosis Sequence Analysis DNA lysosomal storage diseases (LSDs) medicine.disease Doenças Genéticas Lysosomal Storage Diseases 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 diagnostics odyssey biology.protein business Lysosomes Time to diagnosis |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 6355, p 6355 (2020) Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP International Journal of Molecular Sciences Volume 21 Issue 17 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients. This research was partially supported by NORTE2020 (NORTE-01-0246-FEDER-000014 DESVENDAR “DEScobrir, VENcer as Doenças Raras”, FCT (Fundação para a Ciência e a Tecnologia—MCTES, Portugal): project PTDC/BBB-BMD/6301/2014 and UIDB/00211/2020. info:eu-repo/semantics/publishedVersion |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|