Exome sequencing of pashtun familial epilepsy in Pakistan reveals novel variants in LAMA5, KCNQ2 and GNAO1.

backgroundEpilepsy is a heterogeneous neurological disorder characterized by recurrent, unprovoked seizures, with genetic factors playing a major role in its etiology, particularly in consanguineous populations where recessive variants are more prominent.

methodsDetailed clinical history and comprehensive head-to-toe physical examination were performed, followed by EEG and MRI. Genomic DNA from affected individuals was analyzed using exome sequencing (ES) and variants were interpreted using a standardized bioinformatics pipeline according to ACMG guidelines.

resultsIn family EP-36, a homozygous missense variant in KCNQ2 (c.1232C > A; p.Pro411Gln) was identified in individuals with childhood-onset epilepsy and febrile seizures. In family EP-72, a heterozygous variant of uncertain significance in GNAO1 (c.943C > A; p.Pro315Thr) was detected in a patient presenting with generalized tonic-clonic seizures without developmental delay. In family EP-97, a homozygous likely pathogenic variant in LAMA5 (c.9448G > A; p.Gly3150Ser) was associated with neonatal-onset epilepsy and mesial temporal sclerosis. Segregation analysis revealed an autosomal recessive (AR) mode of inheritance in families EP-36 and EP-97, whereas family EP-72 exhibited an autosomal dominant (AD) inheritance pattern. In silico analyses predicted deleterious effects on protein structure and stability for KCNQ2 and LAMA5 variants, with a comparatively milder but potentially destabilizing impact for GNAO1.

conclusionsThis study expands the mutational and phenotypic spectrum of epilepsy-associated genes in a highly consanguineous population and highlights the efficiency of integrating genomic, clinical, and computational approaches for variant interpretation. The findings also suggest a potential recessive contribution of genes traditionally associated with dominant inheritance, warranting further functional validation.