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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
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.
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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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