Tiered analysis of whole-exome sequencing for epilepsy diagnosis

• Published in: Molecular genetics and genomics : MGG Vol. 295; no. 3; pp. 751 - 763
• Main Authors: Dunn, Paul J., Maher, Bridget H., Albury, Cassie L., Stuart, Shani, Sutherland, Heidi G., Maksemous, Neven, Benton, Miles C., Smith, Robert A., Haupt, Larisa M., Griffiths, Lyn R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2020; Springer Nature B.V
• Subjects: Adolescent; Adult; Animal Genetics and Genomics; Biochemistry; Biomarkers - analysis; Biomedical and Life Sciences; Cadherins - genetics; CCM2 protein; Child; Child, Preschool; Cohort Studies; Epilepsy; Epilepsy - diagnosis; Epilepsy - genetics; Exome - genetics; Family studies; Female; Frameshift mutation; Gene expression; Genetic Testing - methods; Genotypes; GTPase-Activating Proteins - genetics; Human Genetics; Humans; Infant; Kv1.2 Potassium Channel - genetics; Life Sciences; Male; Microbial Genetics and Genomics; Missense mutation; Mutation; Next-generation sequencing; Original Article; Phenotypes; Plant Genetics and Genomics; Prognosis; Seizures; Sodium channels (voltage-gated); Whole Exome Sequencing - methods; Next-generation sequencing; Whole exome sequencing; Epilepsy diagnosis; Tiered analysis
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-020-01657-x

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.