Tiered analysis of whole-exome sequencing for epilepsy diagnosis.

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

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.

Afiliación

Dunn PJ; 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.
Maher BH; 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.
Albury CL; 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.
Stuart S; 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.
Sutherland HG; 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.
Maksemous N; 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.
Benton MC; 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.
Smith RA; 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.
Haupt LM; 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.
Griffiths LR; 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. lyn.griffiths@qut.edu.au.

Mol Genet Genomics ; 295(3): 751-763, 2020 May.

Article en En | MEDLINE | ID: mdl-32146541

RESUMEN

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.

Asunto(s)

Biomarcadores/análisis; Epilepsia/diagnóstico; Epilepsia/genética; Secuenciación del Exoma/métodos; Exoma/genética; Mutación; Adolescente; Adulto; Cadherinas/genética; Niño; Preescolar; Estudios de Cohortes; Femenino; Proteínas Activadoras de GTPasa/genética; Pruebas Genéticas/métodos; Humanos; Lactante; Canal de Potasio Kv.1.2/genética; Masculino; Pronóstico; Protocadherinas

Palabras clave

Epilepsy diagnosis; Next-generation sequencing; Tiered analysis; Whole exome sequencing

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Biomarcadores / Epilepsia / Exoma / Secuenciación del Exoma / Mutación Tipo de estudio: Diagnostic_studies / Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Mol Genet Genomics Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA Año: 2020 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania

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