Primary microcephaly (PM) is a developmental disorder of early neuroprogenitors 
that results in reduction of the brain mass, particularly the cortex. To gain 
fresh insight into the pathogenesis of PM, we describe a consanguineous family 
with a novel genetic variant responsible for the disease. We performed 
autozygosity mapping followed by exome sequencing to detect the causal genetic 
variant. Several functional assays in cells expressing the wild-type or mutant 
gene were performed to understand the pathogenesis of the identified mutation. 
We identify a novel mutation in PHC1, a human orthologue of the Drosophila 
polyhomeotic member of polycomb group (PcG), which significantly decreases PHC1 
protein expression, increases Geminin protein level and markedly abolishes the 
capacity to ubiquitinate histone H2A in patient cells. PHC1 depletion in control 
cells similarly enhances Geminin expression and decreases histone H2A 
ubiquitination. The ubiquitination defect and accumulation of Geminin with 
consequent defect in cell cycle are rescued by over-expression of PHC1 in 
patient cells. Although patients with the PHC1 mutation exhibit PM with no overt 
progression of the disease, patient cells also show aberrant DNA damage repair, 
which is rescued by PHC1 overexpression. These findings reveal several cellular 
defects in cells carrying the PHC1 mutation and highlight the role of chromatin 
remodeling in the pathogenesis of PM.