Exploring the genetic landscape of diphtheria, tetanus and pertussis vaccination-associated seizures or subsequent epilepsies.

BACKGROUND

Diphtheria, Tetanus, and whole-cell Pertussis (DTwP) vaccination-associated seizures form the commonest type of serious adverse event following immunization in India and are an important reason for vaccine hesitancy. Our study explored the genetic explanation of DTwP vaccination-associated seizures or subsequent epilepsies.

METHODS

Between March 2017 and March 2019, we screened 67 children with DTwP vaccination-associated seizures or subsequent epilepsies, and of those, we studied 54 without prior seizures or neurodevelopmental deficits. Our study design was cross-sectional with a 1-year follow-up having both retrospective and prospective cases. We performed clinical exome sequencing focused on 157 epilepsy-associated genes and multiplex ligation-dependent probe amplification of the gene at enrolment. We applied the Vineland Social Maturity Scale for neurodevelopmental assessment at follow-up.

FINDINGS

Of 54 children enrolled and underwent genetic testing (median age 37.5 months, interquartile range 7.7-67.2; diagnosis at enrolment: epilepsy 29, febrile seizure 21, and febrile seizure-plus 4), we found 33 pathogenic variants of 12 genes. Of 33 variants, 13 (39%) were novel. Most pathogenic variants were found in gene (n = 21/33; 64%), in 2 children, and 10 children had one variant in , , , , , , , , , and . Five or more seizures (odds ratio [OR] = 5.3, confidence interval [CI]: 1.6-18.4, p = 0.006), drug-resistant epilepsy (OR = 9.8, 95% CI: 2.6-30.7, p = 0.001) and neurodevelopmental impairment (social quotient < 70) (OR = 5.6, 95% CI: 1.65-17.6, p = 0.006) were significant predictors of genetic diagnosis.

INTERPRETATION

Our study provides proof-of-concept for genetic aetiology in children with DTwP vaccination-associated seizures or subsequent epilepsies and has important implications for vaccination policies in developing countries.

FUNDING

International Pediatric Association Foundation, Inc. (IPAF): İhsan Doğramaci research award 2016/2017; Indian Council of Medical Research (ICMR), New Delhi, India: No.3/1/3/JRF-2016/HRD/LS/71/10940.