complex inheritance; digenic inheritance; exome sequencing; primary microcephaly; zebrafish; Animals; Centrosome/metabolism; Databases, Genetic; Humans; Microcephaly/diagnosis; Microcephaly/genetics; Mutation; Open Reading Frames; Phenotype; Signal Transduction; Exome Sequencing; Zebrafish; Genetic Association Studies/methods; Genetic Predisposition to Disease; Inheritance Patterns; Centrosome; Genetic Association Studies; Microcephaly; Whole Exome Sequencing; Genetics; Genetics (clinical)
Abstract :
[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Duerinckx, Sarah ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium ; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium
JACQUEMIN, VALERIE ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Drunat, Séverine; Department of Genetics, Robert Debré University Hospital, APHP, Paris, France ; INSERM UMR 1141, Université de Paris Diderot, Paris, France
Vial, Yoann ; Department of Genetics, Robert Debré University Hospital, APHP, Paris, France ; INSERM UMR 1141, Université de Paris Diderot, Paris, France
Passemard, Sandrine ; Department of Genetics, Robert Debré University Hospital, APHP, Paris, France ; INSERM UMR 1141, Université de Paris Diderot, Paris, France
Perazzolo, Camille; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Massart, Annick; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Soblet, Julie; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ; Department of Genetics, ULB Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium ; Department of Genetics, ULB Center of Human Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
Racapé, Judith; Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
Desmyter, Laurence; Department of Genetics, ULB Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Badoer, Cindy; Department of Genetics, ULB Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Papadimitriou, Sofia; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium ; Artificial Intelligence Lab, Vrije Universiteit Brussel, Brussels, Belgium
Le Borgne, Yann-Aël; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium
Lefort, Anne; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Libert, Frédérick; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
De Maertelaer, Viviane; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Rooman, Marianne; Computational Biology and Bioinformatics, Université Libre de Bruxelles, Brussels, Belgium
Costagliola, Sabine; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Verloes, Alain; Department of Genetics, Robert Debré University Hospital, APHP, Paris, France ; INSERM UMR 1141, Université de Paris Diderot, Paris, France
Lenaerts, Tom; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium ; Artificial Intelligence Lab, Vrije Universiteit Brussel, Brussels, Belgium
Pirson, Isabelle; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Abramowicz, Marc ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium ; Present Address: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
We thank Christelle Golzio for guidance in zebrafish phenotyping, and Raphael Helaers for help in variant filtering. We thank all the patients and families for their participation in this study. This work was supported by ERA‐net E‐Rare Euromicro, the Action de Recherche Concertée (ARC) of the Belgian Fédération Wallonie Bruxelles, the Fonds de la Recherche Scientifique FRS‐FNRS Belgium, the Convention Jean Van Damme of the Fonds Erasme and the Fonds de soutien Marguerite‐Marie Delacroix. It was facilitated by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN‐ITHACA; EU Framework Partnership Agreement ID: 3HP‐HP‐FPA ERN‐01‐2016/739516).We thank Christelle Golzio for guidance in zebrafish phenotyping, and Raphael Helaers for help in variant filtering. We thank all the patients and families for their participation in this study. This work was supported by ERA-net E-Rare Euromicro, the Action de Recherche Concertée (ARC) of the Belgian Fédération Wallonie Bruxelles, the Fonds de la Recherche Scientifique FRS-FNRS Belgium, the Convention Jean Van Damme of the Fonds Erasme and the Fonds de soutien Marguerite-Marie Delacroix. It was facilitated by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA; EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516).
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