Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome

Farah Qaiser; Tara Sadoway; Yue Yin; Quratulain Zulfiqar Ali; Charlotte M Nguyen; Natalie Shum; Ian Backstrom; Paula T Marques; Sepideh Tabarestani; Renato P Munhoz; Timo Krings; Christopher E Pearson; Ryan K C Yuen; Danielle M Andrade

doi:10.1093/braincomms/fcab207

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome

Brain Commun. 2021 Sep 14;3(3):fcab207. doi: 10.1093/braincomms/fcab207. eCollection 2021.

Authors

Farah Qaiser^{1

2

3}, Tara Sadoway³, Yue Yin², Quratulain Zulfiqar Ali³, Charlotte M Nguyen^{1

2}, Natalie Shum^{1

2}, Ian Backstrom², Paula T Marques³, Sepideh Tabarestani³, Renato P Munhoz^{4

5}, Timo Krings^{6

7}, Christopher E Pearson^{1

2}, Ryan K C Yuen^{1

2}, Danielle M Andrade^{3

4

8}

Affiliations

¹ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Canada.
² Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada.
³ Adult Epilepsy Genetics Research Program, Krembil Neurosciences Institute, Toronto Western Hospital, University Health Network, Toronto, Canada.
⁴ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada.
⁵ Neuromodulation Unit and Ataxia Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada.
⁶ Department of Medical Imaging, University of Toronto, Toronto, Canada.
⁷ Division of Neuroradiology, Toronto Western Hospital, University Health Network, Toronto, Canada.
⁸ Epilepsy Program, Krembil Neurosciences Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada.

Abstract

Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole-genome sequencing may provide additional insights into genetic causes of epilepsies of unknown aetiology. Whole-genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole-exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analysed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox-Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox-Gastaut syndrome: a CGG repeat expansion in the 5'untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole-genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox-Gastaut syndrome. This study demonstrates that using whole-genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

Keywords: ATXN80S; DIP2B; Lennox–Gastaut syndrome; tandem repeats; whole-genome sequencing.