Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy

Kavitha Kothur; Katherine Holman; Elizabeth Farnsworth; Gladys Ho; Michelle Lorentzos; Christopher Troedson; Sachin Gupta; Richard Webster; Peter G Procopis; Manoj P Menezes; Jayne Antony; Simone Ardern-Holmes; Russell C Dale; John Christodoulou; Deepak Gill; Bruce Bennetts

doi:10.1016/j.seizure.2018.05.005

Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy

Seizure. 2018 Jul:59:132-140. doi: 10.1016/j.seizure.2018.05.005. Epub 2018 May 28.

Authors

Kavitha Kothur¹, Katherine Holman², Elizabeth Farnsworth², Gladys Ho³, Michelle Lorentzos¹, Christopher Troedson⁴, Sachin Gupta⁴, Richard Webster¹, Peter G Procopis⁵, Manoj P Menezes⁶, Jayne Antony⁴, Simone Ardern-Holmes¹, Russell C Dale¹, John Christodoulou⁷, Deepak Gill¹, Bruce Bennetts⁸

Affiliations

¹ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, The University of Sydney, Sydney, NSW, Australia.
² Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.
³ Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child & Adolescent Health; Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia.
⁴ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁵ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Paediatric and Child health, Camperdown, The University of Sydney, Sydney, Australia.
⁶ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, The University of Sydney, Sydney, NSW, Australia; Paediatric and Child health, Camperdown, The University of Sydney, Sydney, Australia.
⁷ Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute and Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
⁸ Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child & Adolescent Health; Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia. Electronic address: bruce.bennetts@health.nsw.gov.au.

PMID: 29852413
DOI: 10.1016/j.seizure.2018.05.005

Abstract

Purpose: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy.

Method: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants.

Results: The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants.

Conclusion: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.

Keywords: Cost efficacy; Epilepsy; Genetics; Massively parallel sequencing; Yield.

MeSH terms

Adolescent
Child
Child, Preschool
Cost-Benefit Analysis
Epilepsy / diagnosis*
Epilepsy / economics
Epilepsy / genetics*
Female
Genetic Predisposition to Disease
Genetic Testing* / economics
Genetic Testing* / methods
Genetic Variation
High-Throughput Nucleotide Sequencing* / economics
Humans
Infant
Male
Phenotype
Retrospective Studies