Primary microcephaly (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a markedly reduced head circumference, simplified brain gyri, and varying degrees of intellectual disability. To date, more than 20 genes have been implicated in MCPH. Among these, WDR62(WD repeat domain 62), located on chromosome 19q13.12, represents the second most frequently mutated gene after ASPMand is designated as the MCPH2 locus. The WDR62 protein plays a vital role in neuronal progenitor proliferation, spindle pole formation, and neuronal migration during cortical development.
In this study, 33 Pakistani families with clinically diagnosed primary microcephaly were evaluated for linkage to known MCPH loci using microsatellite markers. Several families demonstrated linkage to the MCPH2 locus, indicating a likely involvement of WDR62variants in this cohort. Subsequent direct sequencing of the WDR62gene revealed both previously known and novel pathogenic mutations. These included missense, nonsense, and frameshift variants, many of which co-segregated with the disease phenotype but were absent in 200 ethnically matched control chromosomes.
Clinically, affected individuals with WDR62-related microcephaly typically present with severe congenital microcephaly, developmental delay, and intellectual disability. Neuroimaging findings often reveal simplified gyral patterns, cortical malformations, abnormal hippocampal formation, and occasionally corpus callosum hypoplasia or ventriculomegaly. Molecular studies have shown that loss-of-function mutations in WDR62 impair centrosomal function and disrupt mitotic spindle organization, leading to premature neuronal differentiation and reduced brain.
These results emphasize the key role of WDR62in cortical neurogenesis and further support the genetic diversity and complexity of primary microcephaly across different populations.
WDR62