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Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

BACKGROUND: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-tru...

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Autores principales: Koskenvuo, Juha W., Saarinen, Inka, Ahonen, Saija, Tommiska, Johanna, Weckström, Sini, Seppälä, Eija H., Tuupanen, Sari, Kangas-Kontio, Tiia, Schleit, Jennifer, Heliö, Krista, Hathaway, Julie, Gummesson, Anders, Dahlberg, Pia, Ojala, Tiina H., Vepsäläinen, Ville, Kytölä, Ville, Muona, Mikko, Sistonen, Johanna, Salmenperä, Pertteli, Gentile, Massimiliano, Paananen, Jussi, Myllykangas, Samuel, Alastalo, Tero-Pekka, Heliö, Tiina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857588/
https://www.ncbi.nlm.nih.gov/pubmed/33534821
http://dx.doi.org/10.1371/journal.pone.0245681
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author Koskenvuo, Juha W.
Saarinen, Inka
Ahonen, Saija
Tommiska, Johanna
Weckström, Sini
Seppälä, Eija H.
Tuupanen, Sari
Kangas-Kontio, Tiia
Schleit, Jennifer
Heliö, Krista
Hathaway, Julie
Gummesson, Anders
Dahlberg, Pia
Ojala, Tiina H.
Vepsäläinen, Ville
Kytölä, Ville
Muona, Mikko
Sistonen, Johanna
Salmenperä, Pertteli
Gentile, Massimiliano
Paananen, Jussi
Myllykangas, Samuel
Alastalo, Tero-Pekka
Heliö, Tiina
author_facet Koskenvuo, Juha W.
Saarinen, Inka
Ahonen, Saija
Tommiska, Johanna
Weckström, Sini
Seppälä, Eija H.
Tuupanen, Sari
Kangas-Kontio, Tiia
Schleit, Jennifer
Heliö, Krista
Hathaway, Julie
Gummesson, Anders
Dahlberg, Pia
Ojala, Tiina H.
Vepsäläinen, Ville
Kytölä, Ville
Muona, Mikko
Sistonen, Johanna
Salmenperä, Pertteli
Gentile, Massimiliano
Paananen, Jussi
Myllykangas, Samuel
Alastalo, Tero-Pekka
Heliö, Tiina
author_sort Koskenvuo, Juha W.
collection PubMed
description BACKGROUND: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. METHODS AND RESULTS: We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. CONCLUSION: Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.
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spelling pubmed-78575882021-02-11 Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy Koskenvuo, Juha W. Saarinen, Inka Ahonen, Saija Tommiska, Johanna Weckström, Sini Seppälä, Eija H. Tuupanen, Sari Kangas-Kontio, Tiia Schleit, Jennifer Heliö, Krista Hathaway, Julie Gummesson, Anders Dahlberg, Pia Ojala, Tiina H. Vepsäläinen, Ville Kytölä, Ville Muona, Mikko Sistonen, Johanna Salmenperä, Pertteli Gentile, Massimiliano Paananen, Jussi Myllykangas, Samuel Alastalo, Tero-Pekka Heliö, Tiina PLoS One Research Article BACKGROUND: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. METHODS AND RESULTS: We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. CONCLUSION: Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing. Public Library of Science 2021-02-03 /pmc/articles/PMC7857588/ /pubmed/33534821 http://dx.doi.org/10.1371/journal.pone.0245681 Text en © 2021 Koskenvuo et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Koskenvuo, Juha W.
Saarinen, Inka
Ahonen, Saija
Tommiska, Johanna
Weckström, Sini
Seppälä, Eija H.
Tuupanen, Sari
Kangas-Kontio, Tiia
Schleit, Jennifer
Heliö, Krista
Hathaway, Julie
Gummesson, Anders
Dahlberg, Pia
Ojala, Tiina H.
Vepsäläinen, Ville
Kytölä, Ville
Muona, Mikko
Sistonen, Johanna
Salmenperä, Pertteli
Gentile, Massimiliano
Paananen, Jussi
Myllykangas, Samuel
Alastalo, Tero-Pekka
Heliö, Tiina
Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title_full Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title_fullStr Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title_full_unstemmed Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title_short Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy
title_sort biallelic loss-of-function in nrap is a cause of recessive dilated cardiomyopathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857588/
https://www.ncbi.nlm.nih.gov/pubmed/33534821
http://dx.doi.org/10.1371/journal.pone.0245681
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