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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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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. |
format | Online Article Text |
id | pubmed-7496698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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