Genomic insights into autosomal recessive epilepsy: novel pathogenic variants in ITPA and CLN5 identified in consanguineous families.

backgroundAmong the Pashtun population in Pakistan, familial epilepsy cases remain under-explored at the molecular level. This study aims to find causative variants in genes associated with epilepsy using whole exome sequencing (ES) in consanguineous Pashtun population of Pakistan.

methodsWe took a detailed clinical history followed by head-to-toe physical examination, MRI and EEG test. Afterward, we performed whole exome sequencing followed by variant interpretation using current bioinformatic pipelines based on ACMG guidelines. Then, we performed segregation analysis for the validation of variants among family members to identify the pattern of inheritance.

resultsWe identified novel homozygous pathogenic variant in two families. In family, an unreported frameshift pathogenic variant (c.379dup, p.Thr127Asnfs*11) was identified in the CLN5 gene in two affected siblings presenting with generalized myoclonic epilepsy, vision problems, developmental and motor delay. In family B, a novel homozygous variant (c.136 C > T, p.Gln46*) was identified in the ITPA gene in a male child diagnosed with Developmental and Epileptic Encephalopathy 35 (DEE35). Craniosynostosis was observed in association with the ITPA gene, which have not been reported previously. Other common features were early-onset seizures, developmental delays, microcephaly, and autistic features. Seizures were refractory to multiple antiepileptic drugs in both cases.

conclusionTo the best of our knowledge, this is the first reported case of an ITPA variant in the Pashtun population of Pakistan, with the newly observed association with craniosynostosis providing useful insights for clinicians and researchers. These two novel variants in ITPA and CLN5 cases, expand the genotypic and phenotypic spectrum of epilepsy in consanguineous Pashtun populations of Pakistan. These findings emphasize the importance of ES in the genetic diagnosis of epilepsy in underserved regions and the need for early age genetic testing, and counseling in high-risk communities.