Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1

ABSTRACT Next‐generation sequencing is advancing in low‐ and middle‐income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio‐cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene‐disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease‐causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X‐linked intellectual disability with epilepsy. Our small study demonstrates the promise of next‐generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next‐generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path. The Pashtun population is prone to genetic diseases due to common practice of familial marriage and socio‐cultural isolation. Through exome sequencing of four selected families, we identified causative and candidate variants in TSEN54, MOCS2, and OPHN1.