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; Daniel Nilsson; Martin Engvall; Helena Malmgren; Håkan Thonberg; Maria Pettersson; Britt-Marie Anderlid; Anna Hammarsjö; Hafdis T Helgadottir; Snjolaug Arnardottir; Karin Naess; Inger Nennesmo; Martin Paucar; Helgi Thor Hjartarson; Rayomand Press; Göran Solders; Thomas Sejersen; Anna Lindstrand; Malin Kvarnung

doi:10.3389/fneur.2023.1170005

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

Front Neurol. 2023 May 18:14:1170005. doi: 10.3389/fneur.2023.1170005. eCollection 2023.

Authors

Marlene Ek^{1

2}, Daniel Nilsson^{1

2

3}, Martin Engvall^{1

4}, Helena Malmgren^{1

2}, Håkan Thonberg^{1

2}, Maria Pettersson^{1

2}, Britt-Marie Anderlid^{1

2}, Anna Hammarsjö^{1

2}, Hafdis T Helgadottir^{1

2}, Snjolaug Arnardottir⁵, Karin Naess^{4

6}, Inger Nennesmo⁷, Martin Paucar^{1

2}, Helgi Thor Hjartarson⁸, Rayomand Press⁹, Göran Solders^{5

9}, Thomas Sejersen^{8

10}, Anna Lindstrand^{1

2}, Malin Kvarnung^{1

2}

Affiliations

¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
² Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
³ Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet Science Park, Solna, Sweden.
⁴ Karolinska University Hospital, Centre for Inherited Metabolic Diseases, Stockholm, Sweden.
⁵ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁶ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden.
⁸ Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁹ Department of Clinical Neurophysiology, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Abstract

Introduction: Neuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals.

Methods: In 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.

Results: In 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.

Discussion: Our 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: ataxia; genome sequencing; neuromuscular disorders; repeat expansion; single nucleotide variant; structural variant.

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

Grants and funding

This research was funded by Swedish Research Council, grant number 2019-02078; the Swedish Brain Foundation, grant number FO2022-0256; the Stockholm Regional Council (ALF funding); and the Swedish Rare Diseases Research Foundation (Sällsyntafonden).