PUBLICATION
Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways
- Authors
- Duerinckx, S., Jacquemin, V., Drunat, S., Vial, Y., Passemard, S., Perazzolo, C., Massart, A., Soblet, J., Racapé, J., Desmyter, L., Badoer, C., Papadimitriou, S., Borgne, Y.L., Lefort, A., Libert, F., Maertelaer, V., Rooman, M., Costagliola, S., Verloes, A., Lenaerts, T., Pirson, I., Abramowicz, M.
- ID
- ZDB-PUB-191108-31
- Date
- 2019
- Source
- Human Mutation 41(2): 512-524 (Journal)
- Registered Authors
- Costagliola, Sabine, Pirson, Isabelle
- Keywords
- Primary microcephaly, complex inheritance, digenic inheritance, exome sequencing, zebrafish
- MeSH Terms
-
- Animals
- Centrosome/metabolism*
- Databases, Genetic
- Exome Sequencing
- Genetic Association Studies*/methods
- Genetic Predisposition to Disease*
- Humans
- Inheritance Patterns*
- Microcephaly/diagnosis*
- Microcephaly/genetics*
- Mutation
- Open Reading Frames
- Phenotype
- Signal Transduction
- Zebrafish
- PubMed
- 31696992 Full text @ Hum. Mutat.
Citation
Duerinckx, S., Jacquemin, V., Drunat, S., Vial, Y., Passemard, S., Perazzolo, C., Massart, A., Soblet, J., Racapé, J., Desmyter, L., Badoer, C., Papadimitriou, S., Borgne, Y.L., Lefort, A., Libert, F., Maertelaer, V., Rooman, M., Costagliola, S., Verloes, A., Lenaerts, T., Pirson, I., Abramowicz, M. (2019) Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways. Human Mutation. 41(2):512-524.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping