Copy Number Variations (CNVs) in Refractory Epilepsy of Childhood in Indian Patients
S M Krishna Mohan Mavuru1, Ramshekhar Menon2, Ashalatha Radhakrishnan3
1Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, India, 2Neurology, Neurology Dept, Sree Chitra Tirunal Institute for Medical Sciences & Technology, 3Neurology, Sree Chitra Tirunal Institute for Medical Sciences & Technology
Objective:
To determine the yield and electro-clinical profile of the epilepsy patients with CNVs
Background:
Data regarding pathogenic CNVs as attributed causes of refractory-epilepsy in childhood and developmental-epilepticencephalopathies(DEE) from Indian-subcontinent is lacking.
Design/Methods:
Data was derived from a prospectively maintained cohort of refractory-epilepsy patients of uncertain etiology from a tertiary referral centre for epilepsy in South India. Data of all the patients with refractory-epilepsy who underwent genetic testing was reviewed. Patients with CNVs were identified
and their electroclinical profile was elucidated.
Results:
Total 41 patients(males 24) had CNVs of the 504 patients who underwent genetic testing with age range 4months-15 years age. CNVs were detected using Chromosomalmicroarray(CMA) in 10, clinical/whole exome-sequencing(CES/WES) in 28, MLPA in 2, FISH in 1] with deletions in 20, duplications in 20, 1 patient had 1 deletion and duplication. CNVs size ranged from 311bp to 19.8mb. Most commonly CNVs were seen in Chr 2 and 15 in 7(17%) patients each, with hotspots being 15q11 in 5(12%) followed by Xp22, 22q11 in 3(7.3%) each. CNVs were pathogenic in 11(26.8%), likely-pathogenic in 8(19.5%) while remaining were promising VUS(22; 53.6%). Initial development was normal in 7(17%), while 30(73%) had delay. 9(21%) had developmental regression after seizure onset. 17 had facial dysmorphism and 10 had family history of seizures or neurodevelopmental disorders. Epilepsy syndromes reported were focal in 13, generalised in 7, Dravet in 5, West in 5, LGS in 4, CSWS in 3, unclassifiable-DEE in 3 and Ohtahara in 1. Pathogenic/likely-pathogenic CNVs were detected in 3.5% of CES/WES tests and 26.9% of CMA tests.
Conclusions:
This is the largest study from India studying CNVs in childhood refractory epilepsy and DEEs. Facial dysmoprhism and family history of seizures or NDDs are not essential to suspect CNVs in a given patient. Exome-sequencing can supplement CMA in detecting CNVs in drug-resistant childhood epilepsy of uncertain etiology