Sarah Duerinckx, Sarah Duerinckx, Valérie Jacquemin, Valérie Jacquemin, Séverine Drunat, Séverine Drunat, Yoann Vial, Yoann Vial, Sandrine Passemard, Sandrine Passemard, Camille Perazzolo, Camille Perazzolo, Annick Massart, Annick Massart, Julie Soblet, Julie Soblet, Judith Racapé, Judith Racapé, Laurence Desmyter, Laurence Desmyter, Cindy Badoer, Cindy Badoer, Sofia Papadimitriou, Sofia Papadimitriou, YannAel Le Borgne, YannAel Le Borgne, Anne Lefort, Anne Lefort, Frédérick Libert, Frédérick Libert, Viviane De Maertelaer, Viviane De Maertelaer, Marianne Rooman, Marianne Rooman, Sabine Costagliola, Sabine Costagliola, Alain Verloes, Alain Verloes, Tom Lenaerts, Tom Lenaerts, Isabelle Pirson, Isabelle Pirson, Marc Abramowicz, 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.
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-AL, Lefort, A, Libert, F, Maertelaer, VD, Rooman, M, Costagliola, S, Verloes, A, Lenaerts, T, Pirson, I & Abramowicz, M 2020, 'Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways', Human Mutation, vol. 41, no. 2, pp. 512-524. https://doi.org/10.1002/humu.23948
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.-A. L., Lefort, A., Libert, F., Maertelaer, V. D., Rooman, M., Costagliola, S., Verloes, A., ... Abramowicz, M. (2020). Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways. Human Mutation, 41(2), 512-524. https://doi.org/10.1002/humu.23948
@article{e3cf2762f5934e58a097d3679d55616e,
title = "Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways",
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.",
author = "Sarah Duerinckx and Val{\'e}rie Jacquemin and S{\'e}verine Drunat and Yoann Vial and Sandrine Passemard and Camille Perazzolo and Annick Massart and Julie Soblet and Judith Racap{\'e} and Laurence Desmyter and Cindy Badoer and Sofia Papadimitriou and Borgne, \{Yann-A{\"e}l Le\} and Anne Lefort and Fr{\'e}d{\'e}rick Libert and Maertelaer, \{Viviane De\} and Marianne Rooman and Sabine Costagliola and Alain Verloes and Tom Lenaerts and Isabelle Pirson and Marc Abramowicz",
note = "This article is protected by copyright. All rights reserved.",
year = "2020",
month = feb,
day = "1",
doi = "10.1002/humu.23948",
language = "English",
volume = "41",
pages = "512--524",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "2",
}