Exome sequencing of Pashtun familial Epilepsy in Pakistan reveals novel variants in LAMA5, KCNQ2 and GNAO1

Title : Exome sequencing of Pashtun familial Epilepsy in Pakistan reveals novel variants in LAMA5, KCNQ2 and GNAO1

Abstract:

Background: Epilepsy 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.
Methods: Detailed 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.
Results: In 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.
Conclusions: This 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.

Keywords: Epilepsy; KCNQ2; GNAO1; LAMA5; Consanguinity; MRI; ES; Developmental and epileptic encephalopathy (DEE)

Biography:

Dr. Qaisar Ali is a molecular geneticist and researcher specializing in human neurological disorders, particularly epilepsy and developmental and epileptic encephalopathies. He recently completed his PhD in Molecular Genetics from the University of Peshawar. He has over five years of experience in scientific writing, research, and bioinformatics. His work focuses on identifying pathogenic variants in consanguineous Pashtoon families using whole exome sequencing and computational analyses. He has collaborated with international institutions including the University of Tübingen, Germany, and Acibadem University, Istanbul, Türkiye. He has also contributed to academic workshops and research initiatives in neurogenetics and translational medicine.