DOI

  • Sarah Duerinckx
  • Valérie Jacquemin
  • Séverine Drunat
  • Yoann Vial
  • Sandrine Passemard
  • Camille Perazzolo
  • Annick Massart
  • Julie Soblet
  • Judith Racapé
  • Laurence Desmyter
  • Cindy Badoer
  • Anne Lefort
  • Frédérick Libert
  • Viviane De Maertelaer
  • Sabine Costagliola
  • Alain Verloes
  • Isabelle Pirson
  • Marc Abramowicz

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 PM patients, and genome-edited zebrafish modeling for digenic inheritance of PM. Exomes of PM patients 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 PM patients, 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusE-pub ahead of print - 7 Nov 2019

ID: 48348982