Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein truncating mutations of ASPM.

Autosomal primary microcephaly (MCPH) is a heterogenetic disorder that affects brain's cerebral cortex size and leads to reduction in cranial vault. Along with the hallmark feature of reduced head circumference, microcephalic patients also exhibit variable degree of intellectual disability as well. Genetic studies have reported twenty-eight MCPH genes, most of which produces microtubule associated proteins and involved in the cell division. Herein this study, 14 patients from seven Pashtun origin Pakistani families of primary microcephaly was analyzed. Mutation analysis was performed through targeted Sanger DNA sequencing, on the basis of phenotype linked genetic makeup. Genetic analysis in one family found a novel pathogenic DNA change in ASPM gene (NM_018136.4:c.3871dupGA), while rest of the families revealed recurrent non-sense mutation c.3978G>A (p.Trp1326*) in the same gene. The novel reported frameshift insertion presumably truncate the protein p.(Lys1291Glyfs*14), and delete the N-terminus domains. Identification of novel ASPM truncating mutation expand the mutational spectrum of ASPM gene, while, mapping of recurrent mutation c.3978G>A (p.Trp1326*) will aid in establishing its founder effect in KPK inhabitant population of Pakistan, and should be suggestively screened for premarital counselling of MCPH susceptible families. Most of the recruited families are related with first degree consanguinity. Hence, all the family elders were counselled to avoid intra-familial marriages. This article is protected by copyright. All rights reserved.