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Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores
BACKGROUND: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome‐wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is ex...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009911/ https://www.ncbi.nlm.nih.gov/pubmed/36468602 http://dx.doi.org/10.1002/mgg3.2109 |
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author | Ishorst, Nina Henschel, Leonie Thieme, Frederic Drichel, Dmitriy Sivalingam, Sugirthan Mehrem, Sarah L. Fechtner, Ariane C. Fazaal, Julia Welzenbach, Julia Heimbach, André Maj, Carlo Borisov, Oleg Hausen, Jonas Raff, Ruth Hoischen, Alexander Dixon, Michael Rada‐Iglesias, Alvaro Bartusel, Michaela Rojas‐Martinez, Augusto Aldhorae, Khalid Braumann, Bert Kruse, Teresa Kirschneck, Christian Spanier, Gerrit Reutter, Heiko Nowak, Stefanie Gölz, Lina Knapp, Michael Buness, Andreas Krawitz, Peter Nöthen, Markus M. Nothnagel, Michael Becker, Tim Ludwig, Kerstin U. Mangold, Elisabeth |
author_facet | Ishorst, Nina Henschel, Leonie Thieme, Frederic Drichel, Dmitriy Sivalingam, Sugirthan Mehrem, Sarah L. Fechtner, Ariane C. Fazaal, Julia Welzenbach, Julia Heimbach, André Maj, Carlo Borisov, Oleg Hausen, Jonas Raff, Ruth Hoischen, Alexander Dixon, Michael Rada‐Iglesias, Alvaro Bartusel, Michaela Rojas‐Martinez, Augusto Aldhorae, Khalid Braumann, Bert Kruse, Teresa Kirschneck, Christian Spanier, Gerrit Reutter, Heiko Nowak, Stefanie Gölz, Lina Knapp, Michael Buness, Andreas Krawitz, Peter Nöthen, Markus M. Nothnagel, Michael Becker, Tim Ludwig, Kerstin U. Mangold, Elisabeth |
author_sort | Ishorst, Nina |
collection | PubMed |
description | BACKGROUND: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome‐wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. METHODS: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent‐trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV‐carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population‐matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome‐wide association data, expression, protein–protein‐interactions), were used for final prioritization. CONCLUSION: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re‐sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations. |
format | Online Article Text |
id | pubmed-10009911 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100099112023-03-14 Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores Ishorst, Nina Henschel, Leonie Thieme, Frederic Drichel, Dmitriy Sivalingam, Sugirthan Mehrem, Sarah L. Fechtner, Ariane C. Fazaal, Julia Welzenbach, Julia Heimbach, André Maj, Carlo Borisov, Oleg Hausen, Jonas Raff, Ruth Hoischen, Alexander Dixon, Michael Rada‐Iglesias, Alvaro Bartusel, Michaela Rojas‐Martinez, Augusto Aldhorae, Khalid Braumann, Bert Kruse, Teresa Kirschneck, Christian Spanier, Gerrit Reutter, Heiko Nowak, Stefanie Gölz, Lina Knapp, Michael Buness, Andreas Krawitz, Peter Nöthen, Markus M. Nothnagel, Michael Becker, Tim Ludwig, Kerstin U. Mangold, Elisabeth Mol Genet Genomic Med Original Articles BACKGROUND: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome‐wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. METHODS: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent‐trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV‐carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population‐matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome‐wide association data, expression, protein–protein‐interactions), were used for final prioritization. CONCLUSION: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re‐sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations. John Wiley and Sons Inc. 2022-12-05 /pmc/articles/PMC10009911/ /pubmed/36468602 http://dx.doi.org/10.1002/mgg3.2109 Text en © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://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 | Original Articles Ishorst, Nina Henschel, Leonie Thieme, Frederic Drichel, Dmitriy Sivalingam, Sugirthan Mehrem, Sarah L. Fechtner, Ariane C. Fazaal, Julia Welzenbach, Julia Heimbach, André Maj, Carlo Borisov, Oleg Hausen, Jonas Raff, Ruth Hoischen, Alexander Dixon, Michael Rada‐Iglesias, Alvaro Bartusel, Michaela Rojas‐Martinez, Augusto Aldhorae, Khalid Braumann, Bert Kruse, Teresa Kirschneck, Christian Spanier, Gerrit Reutter, Heiko Nowak, Stefanie Gölz, Lina Knapp, Michael Buness, Andreas Krawitz, Peter Nöthen, Markus M. Nothnagel, Michael Becker, Tim Ludwig, Kerstin U. Mangold, Elisabeth Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title_full | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title_fullStr | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title_full_unstemmed | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title_short | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
title_sort | identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009911/ https://www.ncbi.nlm.nih.gov/pubmed/36468602 http://dx.doi.org/10.1002/mgg3.2109 |
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