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

Abstract

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 SCN1A 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 SCN1A gene (n = 21/33; 64%), SCN8A in 2 children, and 10 children had one variant in CDKL5, DEPDC5, GNAO1, KCNA2, KCNT1, KCNQ2, NPRL3, PCDH19, RHOBTB2, and SLC2A1. 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.

Keywords: Diphtheria-tetanus-pertussis; Neurodevelopment; Next-generation sequencing; Seizure; Vaccine; Vaccine hesitancy.

Fig. 1

Genetic outcome with syndromic diagnoses at the time of recruitment. (a) Yield in 54 children according to syndromic diagnoses of epilepsy or seizures at recruitment. FS = Febrile seizure, MEI = Myoclonic epilepsy in infancy, ICEGTC = Intractable childhood epilepsy with generalized tonic-clonic seizures. (b) Percentage wise distribution of 33 pathogenic variants according to epilepsy or seizures diagnoses.

Fig. 2

Location of SCN1A gene variants in our study. Pathogenic variants are missense, nonsense, splice-site, and frameshift deletion, which are spread across the gene.

Fig. 3

Association of genetic diagnosis and phenotypic characteristics. Neurodevelopmental impairment (OR = 5.6, 95% CI: 1.65–17.6, p = 0.006); Drug-resistant epilepsy (OR = 9.8, 95% CI: 2.6–30.7, p = 0.001); No. of seizures in infancy ≥5 (OR = 5.3, CI: 1.6–18.4, p = 0.006 are seen significantly associated with genetic pathogenicity, based on Fisher's exact test.