Primary microcephaly (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by reduced brain and intellectual disability, with more than 20 genes identified to date. Among these, MCPH1(microcephalin), located on chromosome 8p23.1, is one of the earliest genes associated with the disorder (designated MCPH1 locus). Mutations in MCPH1disrupt DNA damage response and cell cycle regulation, particularly affecting neuroprogenitor proliferation during cortical development. In this study, 33 Pakistani families diagnosed with primary microcephaly were analyzed for linkage to known MCPH loci using microsatellite markers.
Several families showed linkage to the MCPH1 locus, suggesting a potential contribution of MCPH1variants in this cohort. Subsequent direct sequencing of the MCPH1gene identified both previously reported and novel pathogenic variants. Notably, several missense and truncating mutations segregated with the disease phenotype within affected families but were absent in 200 ethnically matched control chromosomes. These findings reinforce the genetic heterogeneity of primary microcephaly and highlight the critical role of MCPH1in maintaining genomic stability and proper neurogenesis during human brain development.
MCPH1