TY - JOUR
T1 - Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways
AU - Duerinckx, Sarah
AU - Jacquemin, Valérie
AU - Drunat, Séverine
AU - Vial, Yoann
AU - Passemard, Sandrine
AU - Perazzolo, Camille
AU - Massart, Annick
AU - Soblet, Julie
AU - Racapé, Judith
AU - Desmyter, Laurence
AU - Badoer, Cindy
AU - Papadimitriou, Sofia
AU - Borgne, Yann-Aël Le
AU - Lefort, Anne
AU - Libert, Frédérick
AU - Maertelaer, Viviane De
AU - Rooman, Marianne
AU - Costagliola, Sabine
AU - Verloes, Alain
AU - Lenaerts, Tom
AU - Pirson, Isabelle
AU - Abramowicz, Marc
N1 - This article is protected by copyright. All rights reserved.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075718165&partnerID=8YFLogxK
U2 - 10.1002/humu.23948
DO - 10.1002/humu.23948
M3 - Article
C2 - 31696992
VL - 41
SP - 512
EP - 524
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 2
ER -