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...
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BMJ Publishing Group
2021-12-01
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| Series: | Open Heart |
| Online Access: | https://openheart.bmj.com/content/8/2/e001789.full |
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| author | Raquel Yotti Francisco Fernández-Avilés Javier Bermejo Ana Isabel Fernandez Cristina Gómez Constancio Medrano Irene Méndez Maria Ángeles Espinosa Sofía Cuenca Rebeca Lorca José Fernando Rodríguez Maria Tamargo Marta García-Montero Silvia Vilches Nélida Vázquez Reyes Álvarez |
| author_facet | Raquel Yotti Francisco Fernández-Avilés Javier Bermejo Ana Isabel Fernandez Cristina Gómez Constancio Medrano Irene Méndez Maria Ángeles Espinosa Sofía Cuenca Rebeca Lorca José Fernando Rodríguez Maria Tamargo Marta García-Montero Silvia Vilches Nélida Vázquez Reyes Álvarez |
| author_sort | Raquel Yotti |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-f2ebf40c67ea4225b97c7ec6c7a44264 |
| institution | Kabale University |
| issn | 2053-3624 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | BMJ Publishing Group |
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| series | Open Heart |
| spelling | doaj-art-f2ebf40c67ea4225b97c7ec6c7a442642024-11-11T12:45:10ZengBMJ Publishing GroupOpen Heart2053-36242021-12-018210.1136/openhrt-2021-001789Founder mutation in myosin-binding protein C with an early onset and a high penetrance in malesRaquel Yotti0Francisco Fernández-Avilés1Javier Bermejo2Ana Isabel Fernandez3Cristina Gómez4Constancio Medrano5Irene Méndez6Maria Ángeles Espinosa7Sofía Cuenca8Rebeca Lorca9José Fernando Rodríguez10Maria Tamargo11Marta García-Montero12Silvia Vilches13Nélida Vázquez14Reyes Álvarez15Instituto de Salud Carlos III, Madrid, Spain11 Department of Cardiology, General University Gregorio Marañón Hospital, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCIBERCV, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainInstituto de Investigación Sanitaria Gregorio Marañón, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainFacultad de Medicina, Universidad Complutense, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCIBERCV, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainCardiology, Hospital General Universitario Gregorio Marañón, Madrid, SpainInstituto de Investigación Sanitaria Gregorio Marañón, Madrid, SpainObjective 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.https://openheart.bmj.com/content/8/2/e001789.full |
| spellingShingle | Raquel Yotti Francisco Fernández-Avilés Javier Bermejo Ana Isabel Fernandez Cristina Gómez Constancio Medrano Irene Méndez Maria Ángeles Espinosa Sofía Cuenca Rebeca Lorca José Fernando Rodríguez Maria Tamargo Marta García-Montero Silvia Vilches Nélida Vázquez Reyes Álvarez Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males Open Heart |
| 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 |
| url | https://openheart.bmj.com/content/8/2/e001789.full |
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