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Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between  Aspm  and  Wdr62  have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome‐edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in  CEP152 ). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non‐centrosomal gene  casc5  −/− produced a severe PM phenotype, that was not modified by centrosomal genes  aspm  or  wdr62  invalidation. A digenic, quadriallelic PM phenotype was produced by  aspm  and  wdr62 . Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between  casc5  and  aspm  or  wdr62  further delineates centrosomal and non‐centrosomal pathways in PM.

Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways