A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability

Abstract

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

Fig. 1. Pedigree chart for siblings 37 and 39 who carry an MBD5 variant, inherited from an unaffected mother with a somatic variant.

a () Probands: Epilepsy, history of febrile seizures, mild/moderate intellectual disability (ID), ±Asperger syndrome. () Sister of probands: Moderate ID, behavioural problems, no epilepsy. () Epilepsy, no ID. Variant of Interest: MBD5 p.(D242fs) ± = Heterozygote for MBD5 p. (D242fs). (±) = Mosaic heterozygote for MBD5 p.(D242fs). −/− = Tested negative for MBD5 p. (D242fs). b II₅ Unaffected father of proband. II₆ Unaffected mother of probands. II₇ Developed epilepsy at 52 years. III₃ Proband (Patient 37): Epilepsy, mild intellectual disability (ID), Aspeger syndrome, history of febrile seizures. Tetralogy of Fallot at birth. III₄ Unaffected twin sister. III₆ Moderate ID, complex mood disorder, challenging behaviour. III₇ Proband (Patient 39): Moderate ID, epilepsy, history of febrile seizures. III₁₀ Few seizures as teenager. No seizures now.