Frontiers in Neurology (May 2023)
Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders
- Marlene Ek,
- Marlene Ek,
- Daniel Nilsson,
- Daniel Nilsson,
- Daniel Nilsson,
- Martin Engvall,
- Martin Engvall,
- Helena Malmgren,
- Helena Malmgren,
- Håkan Thonberg,
- Håkan Thonberg,
- Maria Pettersson,
- Maria Pettersson,
- Britt-Marie Anderlid,
- Britt-Marie Anderlid,
- Anna Hammarsjö,
- Anna Hammarsjö,
- Hafdis T. Helgadottir,
- Hafdis T. Helgadottir,
- Snjolaug Arnardottir,
- Karin Naess,
- Karin Naess,
- Inger Nennesmo,
- Martin Paucar,
- Martin Paucar,
- Helgi Thor Hjartarson,
- Rayomand Press,
- Göran Solders,
- Göran Solders,
- Thomas Sejersen,
- Thomas Sejersen,
- Anna Lindstrand,
- Anna Lindstrand,
- Malin Kvarnung,
- Malin Kvarnung
Affiliations
- Marlene Ek
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Marlene Ek
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Daniel Nilsson
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Daniel Nilsson
- Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet Science Park, Solna, Sweden
- Martin Engvall
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Martin Engvall
- Karolinska University Hospital, Centre for Inherited Metabolic Diseases, Stockholm, Sweden
- Helena Malmgren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Helena Malmgren
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Håkan Thonberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Håkan Thonberg
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Maria Pettersson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Maria Pettersson
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Britt-Marie Anderlid
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Britt-Marie Anderlid
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Anna Hammarsjö
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Anna Hammarsjö
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Hafdis T. Helgadottir
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Hafdis T. Helgadottir
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Snjolaug Arnardottir
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
- Karin Naess
- Karolinska University Hospital, Centre for Inherited Metabolic Diseases, Stockholm, Sweden
- Karin Naess
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- Inger Nennesmo
- Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden
- Martin Paucar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Martin Paucar
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Helgi Thor Hjartarson
- Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Rayomand Press
- Department of Clinical Neurophysiology, Karolinska University Hospital, Stockholm, Sweden
- Göran Solders
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
- Göran Solders
- Department of Clinical Neurophysiology, Karolinska University Hospital, Stockholm, Sweden
- Thomas Sejersen
- Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Thomas Sejersen
- 0Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Anna Lindstrand
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Anna Lindstrand
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Malin Kvarnung
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Malin Kvarnung
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- DOI
- https://doi.org/10.3389/fneur.2023.1170005
- Journal volume & issue
-
Vol. 14
Abstract
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.
Keywords
- neuromuscular disorders
- genome sequencing
- single nucleotide variant
- structural variant
- repeat expansion
- ataxia