Genetic Analysis of Families with Microcephaly and Epilepsy

Abstract

Microcephaly is a neurodevelopmental disorder, that mainly manifests at birth or during early childhood. Autosomal recessive primary microcephaly (MCPH) is the most common type of microcephaly, characterized by small head circumference, ID, and in some cases short stature, epilepsy, and speech impairment. It falls in the category of non-syndromic microcephaly and mutations in 30 genes have been reported till now. Out of these 30 genes, ASPM is the most frequently mutated gene in Pakistan and worldwide, accounting for more than 50% MCPH cases. Epilepsy is frequently observed in MCPH patients carrying mutations in ASPM. This study was aimed to perform genetic analysis on five families (A, B, C, D, and E) with microcephaly and epilepsy and used sanger sequencing to screen specific exons of ASPM gene. Literature search was performed to identify candidate exons and yielded 21 studies which included 48 patients with MCPH and epilepsy phenotype, exons 17,18, 23, and 24 were selected for sequencing as these are the most frequently mutated ASPM exons in individuals with microcephaly and epilepsy. DNA samples from the proband of each family were sequenced to identify pathogenic variants. Sanger sequencing identified one pathogenic variant c.4913T>G (p.V1638G) in family A, which was not reported in public databases and in silico analysis confirmed its disease causing and splice altering effect. No pathogenic variant was identified in other four families (B, C, D, and E) however some SNPs were found. Hence, further research will be required to find the disease-causing variants in the remaining four families. Keywords: Microcephaly, MCPH, Epilepsy, ASPM