Tiered analysis of whole-exome sequencing for epilepsy diagnosis

Molecular Genetics and Genomics : MGG
Paul J DunnLyn R Griffiths

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 hav...Continue Reading

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Citations

May 30, 2020·Biomedicines·Neven MaksemousLyn R Griffiths
May 2, 2021·Molecular and Cellular Neurosciences·Claire S LeblondThomas Bourgeron

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Methods Mentioned

BETA
acetylation
exome sequencing
chip
imaging techniques
glycosylation
chromosomal aberrations

Software Mentioned

ClinVar
PredictSNP2
Integrative Genomics Viewer
CADD
MT Mutation Taster
FunSeq2
DANN
FATHM
Ion [UNK]
GWAVA

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