Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Details

Serval ID
serval:BIB_D620C1C3B2CE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.
Journal
Human mutation
Author(s)
Duerinckx S., Jacquemin V., Drunat S., Vial Y., Passemard S., Perazzolo C., Massart A., Soblet J., Racapé J., Desmyter L., Badoer C., Papadimitriou S., Le Borgne Y.A., Lefort A., Libert F., De Maertelaer V., Rooman M., Costagliola S., Verloes A., Lenaerts T., Pirson I., Abramowicz M.
ISSN
1098-1004 (Electronic)
ISSN-L
1059-7794
Publication state
Published
Issued date
07/11/2019
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
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.
Keywords
complex inheritance, digenic inheritance, exome sequencing, primary microcephaly, zebrafish
Pubmed
Web of science
Open Access
Yes
Create date
06/02/2020 11:29
Last modification date
09/01/2021 6:26
Usage data