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Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males

OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A is a founder pathogenic variant, (2) describe the phenotype an...

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Autores principales: Méndez, Irene, Fernández, Ana Isabel, Espinosa, Maria Ángeles, Cuenca, Sofía, Lorca, Rebeca, Rodríguez, José Fernando, Tamargo, Maria, García-Montero, Marta, Gómez, Cristina, Vilches, Silvia, Vázquez, Nélida, Álvarez, Reyes, Medrano, Constancio, Yotti, Raquel, Fernández-Avilés, Francisco, Bermejo, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483030/
https://www.ncbi.nlm.nih.gov/pubmed/34588271
http://dx.doi.org/10.1136/openhrt-2021-001789
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author Méndez, Irene
Fernández, Ana Isabel
Espinosa, Maria Ángeles
Cuenca, Sofía
Lorca, Rebeca
Rodríguez, José Fernando
Tamargo, Maria
García-Montero, Marta
Gómez, Cristina
Vilches, Silvia
Vázquez, Nélida
Álvarez, Reyes
Medrano, Constancio
Yotti, Raquel
Fernández-Avilés, Francisco
Bermejo, Javier
author_facet Méndez, Irene
Fernández, Ana Isabel
Espinosa, Maria Ángeles
Cuenca, Sofía
Lorca, Rebeca
Rodríguez, José Fernando
Tamargo, Maria
García-Montero, Marta
Gómez, Cristina
Vilches, Silvia
Vázquez, Nélida
Álvarez, Reyes
Medrano, Constancio
Yotti, Raquel
Fernández-Avilés, Francisco
Bermejo, Javier
author_sort Méndez, Irene
collection PubMed
description OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. METHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149–1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. RESULTS: MYBPC3 c.2149–1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149–1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. CONCLUSIONS: MYBPC3 c.2149–1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.
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spelling pubmed-84830302021-10-08 Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males Méndez, Irene Fernández, Ana Isabel Espinosa, Maria Ángeles Cuenca, Sofía Lorca, Rebeca Rodríguez, José Fernando Tamargo, Maria García-Montero, Marta Gómez, Cristina Vilches, Silvia Vázquez, Nélida Álvarez, Reyes Medrano, Constancio Yotti, Raquel Fernández-Avilés, Francisco Bermejo, Javier Open Heart Heart Failure and Cardiomyopathies OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. METHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149–1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. RESULTS: MYBPC3 c.2149–1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149–1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. CONCLUSIONS: MYBPC3 c.2149–1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes. BMJ Publishing Group 2021-09-29 /pmc/articles/PMC8483030/ /pubmed/34588271 http://dx.doi.org/10.1136/openhrt-2021-001789 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Heart Failure and Cardiomyopathies
Méndez, Irene
Fernández, Ana Isabel
Espinosa, Maria Ángeles
Cuenca, Sofía
Lorca, Rebeca
Rodríguez, José Fernando
Tamargo, Maria
García-Montero, Marta
Gómez, Cristina
Vilches, Silvia
Vázquez, Nélida
Álvarez, Reyes
Medrano, Constancio
Yotti, Raquel
Fernández-Avilés, Francisco
Bermejo, Javier
Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title_full Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title_fullStr Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title_full_unstemmed Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title_short Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
title_sort founder mutation in myosin-binding protein c with an early onset and a high penetrance in males
topic Heart Failure and Cardiomyopathies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483030/
https://www.ncbi.nlm.nih.gov/pubmed/34588271
http://dx.doi.org/10.1136/openhrt-2021-001789
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