Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders

Frontiers in Neurology

Neurology

Rayomand Press¹  Maria Pettersson²  Britt-Marie Anderlid²  Malin Kvarnung²  Helena Malmgren²  Anna Hammarsjö²  Håkan Thonberg²  Anna Lindstrand²  Marlene Ek²  Hafdis T. Helgadottir²  Martin Paucar²  Daniel Nilsson³  Martin Engvall⁴  Snjolaug Arnardottir⁵  Göran Solders⁶  Helgi Thor Hjartarson⁷  Thomas Sejersen⁸  Inger Nennesmo⁹  Karin Naess^1,10 

[1] Department of Clinical Neurophysiology, Karolinska University Hospital, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet Science Park, Solna, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Karolinska University Hospital, Centre for Inherited Metabolic Diseases, Stockholm, Sweden;Department of Neurology, Karolinska University Hospital, Stockholm, Sweden;Department of Neurology, Karolinska University Hospital, Stockholm, Sweden;Department of Clinical Neurophysiology, Karolinska University Hospital, Stockholm, Sweden;Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden;Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden;Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden;Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden;Karolinska University Hospital, Centre for Inherited Metabolic Diseases, Stockholm, Sweden;Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;

关键词: neuromuscular disorders;    genome sequencing;    single nucleotide variant;    structural variant;    repeat expansion;    ataxia;   

DOI  :  10.3389/fneur.2023.1170005

 received in 2023-02-20, accepted in 2023-04-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionNeuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals.MethodsIn this study, 861 patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added.ResultsIn the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes.DiscussionOur results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders.

【 授权许可】

Unknown   
Copyright © 2023 Ek, Nilsson, Engvall, Malmgren, Thonberg, Pettersson, Anderlid, Hammarsjö, Helgadottir, Arnardottir, Naess, Nennesmo, Paucar, Hjartarson, Press, Solders, Sejersen, Lindstrand and Kvarnung.