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Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways

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, ho...

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Autores principales: Duerinckx, Sarah, Jacquemin, Valérie, Drunat, Séverine, Vial, Yoann, Passemard, Sandrine, Perazzolo, Camille, Massart, Annick, Soblet, Julie, Racapé, Judith, Desmyter, Laurence, Badoer, Cindy, Papadimitriou, Sofia, Le Borgne, Yann‐Aël, Lefort, Anne, Libert, Frédérick, De Maertelaer, Viviane, Rooman, Marianne, Costagliola, Sabine, Verloes, Alain, Lenaerts, Tom, Pirson, Isabelle, Abramowicz, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496698/
https://www.ncbi.nlm.nih.gov/pubmed/31696992
http://dx.doi.org/10.1002/humu.23948
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author Duerinckx, Sarah
Jacquemin, Valérie
Drunat, Séverine
Vial, Yoann
Passemard, Sandrine
Perazzolo, Camille
Massart, Annick
Soblet, Julie
Racapé, Judith
Desmyter, Laurence
Badoer, Cindy
Papadimitriou, Sofia
Le Borgne, Yann‐Aël
Lefort, Anne
Libert, Frédérick
De Maertelaer, Viviane
Rooman, Marianne
Costagliola, Sabine
Verloes, Alain
Lenaerts, Tom
Pirson, Isabelle
Abramowicz, Marc
author_facet Duerinckx, Sarah
Jacquemin, Valérie
Drunat, Séverine
Vial, Yoann
Passemard, Sandrine
Perazzolo, Camille
Massart, Annick
Soblet, Julie
Racapé, Judith
Desmyter, Laurence
Badoer, Cindy
Papadimitriou, Sofia
Le Borgne, Yann‐Aël
Lefort, Anne
Libert, Frédérick
De Maertelaer, Viviane
Rooman, Marianne
Costagliola, Sabine
Verloes, Alain
Lenaerts, Tom
Pirson, Isabelle
Abramowicz, Marc
author_sort Duerinckx, Sarah
collection PubMed
description 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.
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spelling pubmed-74966982020-09-25 Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways Duerinckx, Sarah Jacquemin, Valérie Drunat, Séverine Vial, Yoann Passemard, Sandrine Perazzolo, Camille Massart, Annick Soblet, Julie Racapé, Judith Desmyter, Laurence Badoer, Cindy Papadimitriou, Sofia Le Borgne, Yann‐Aël Lefort, Anne Libert, Frédérick De Maertelaer, Viviane Rooman, Marianne Costagliola, Sabine Verloes, Alain Lenaerts, Tom Pirson, Isabelle Abramowicz, Marc Hum Mutat Research Articles 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. John Wiley and Sons Inc. 2019-11-27 2020-02 /pmc/articles/PMC7496698/ /pubmed/31696992 http://dx.doi.org/10.1002/humu.23948 Text en © 2019 The Authors. Human Mutation Published by Wiley Periodicals LLC This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Duerinckx, Sarah
Jacquemin, Valérie
Drunat, Séverine
Vial, Yoann
Passemard, Sandrine
Perazzolo, Camille
Massart, Annick
Soblet, Julie
Racapé, Judith
Desmyter, Laurence
Badoer, Cindy
Papadimitriou, Sofia
Le Borgne, Yann‐Aël
Lefort, Anne
Libert, Frédérick
De Maertelaer, Viviane
Rooman, Marianne
Costagliola, Sabine
Verloes, Alain
Lenaerts, Tom
Pirson, Isabelle
Abramowicz, Marc
Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title_full Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title_fullStr Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title_full_unstemmed Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title_short Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
title_sort digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496698/
https://www.ncbi.nlm.nih.gov/pubmed/31696992
http://dx.doi.org/10.1002/humu.23948
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