The genetics of congenitally small brains.

Primary microcephaly (PM) refers to a congenitally small brain, resulting from insufficient prenatal production of neurons, and serves as a model disease for brain volumic development. Known PM genes delineate several cellular pathways, among which the centriole duplication pathway, which provide interesting clues about the cellular mechanisms involved. The general interest of the genetic dissection of PM is illustrated by the convergence of Zika virus infection and PM gene mutations on congenital microcephaly, with CENPJ/CPAP emerging as a key target. Physical (protein-protein) and genetic (digenic inheritance) interactions of Wdr62 and Aspm have been demonstrated in mice, and should now be sought in humans using high throughput parallel sequencing of multiple PM genes in PM patients and control subjects, in order to categorize mutually interacting genes, hence delineating functional pathways in vivo in humans.