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Tiered analysis of whole-exome sequencing for epilepsy diagnosis

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Abstract

It is thought that despite highly variable phenotypic expression, 70—80% of all epileptic cases are caused by one or more genetic mutations. Next generation sequencing technologies, such as whole exome sequencing (WES), can be used in a diagnostic or research setting to identify genetic mutations which may have significant prognostic implications for patients and their families. In this study, 398 genes associated with epilepsy or recurrent seizures were stratified into tiers based on genotype–phenotype concordance, tissue gene expression, frequency of affected individuals with mutations and evidence from functional and family studies. WES was completed on 14 DNA samples (2 with known mutations in SCN1A and 12 with no known mutations) from individuals diagnosed with epilepsy using an Ion AmpliSeq approach. WES confirmed positive SCN1A mutations in two samples. In n = 5/12 samples (S-3 to -14) we identified potentially causative mutations across five different genes. S-5 was identified to have a novel missense mutation in CCM2; S-6 a novel frameshift mutation identified in ADGRV1; S-10 had a previously reported pathogenic mutation in PCDH19, whilst a novel missense mutation in PCDH19 was shown in S-12; and S-13 identified to have separate missense mutations in KCNA2 and NPRL3. The application of WES followed by a targeted variant prioritization approach allowed for the discovery of potentially causative mutations in our cohort of previously undiagnosed epilepsy patients.

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Funding

This work was supported by Corbett philanthropic research funding and utilized infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia—Queensland Node Project.

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  1. Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD, 4059, Australia

    Paul J. Dunn, Bridget H. Maher, Cassie L. Albury, Shani Stuart, Heidi G. Sutherland, Neven Maksemous, Miles C. Benton, Robert A. Smith, Larisa M. Haupt & Lyn R. Griffiths

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  1. Paul J. Dunn
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Correspondence to Lyn R. Griffiths.

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PJD, BHM, CLA, SS, HGS, NM, MCB, RAS, LMH and LRG declare that they have no conflict of interest.

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All procedures in the study involving informed consent for human participants were performed in accordance with ethical standards approved by Queensland University of Technology human research ethics committee (Approval No. 1400000748) and within the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Communicated by Stefan Hohmann.

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Dr. Cassie Albury has recently moved employment to Abacus Dx, Dr. Miles Benton has moved employment to the Institute of Environmental Science and Research Ltd (ESR) and Dr. Shani Stuart is now employed at the Peter McCallum Cancer Centre.

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Dunn, P.J., Maher, B.H., Albury, C.L. et al. Tiered analysis of whole-exome sequencing for epilepsy diagnosis. Mol Genet Genomics 295, 751–763 (2020). https://doi.org/10.1007/s00438-020-01657-x

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