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

Méndez, Irene; Fernández, Ana; Espinosa, María Ángeles; Cuenca, Sofía; Lorca, Rebeca; Rodríguez, J. F.; Tamargo, María; Montero, Marta García; Gómez, Cristina; Vilches, Silvia; Vázquez, Nélida; Álvarez, Reyes; Medrano, Constancio; Yotti, Raquel; Fernández‐Avilés, Francisco; Bermejo, Javier

doi:10.1136/openhrt-2021-001789

Cited by 8 publications

(11 citation statements)

References 33 publications

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“…This is in line with the results of other Spanish and international studies carried out in large populations of patients with HCM [ 29 , 30 , 31 ]. However, other published cohorts have found significant differences in the onset age, with men being younger at diagnosis [ 10 , 31 , 32 ]. We postulate a possible protective role of endocrine factors in women [ 10 ] or a lack of attention to early signs of disease in women and the absence of any special recommendation for screening programs [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, other published cohorts have found significant differences in the onset age, with men being younger at diagnosis [ 10 , 31 , 32 ]. We postulate a possible protective role of endocrine factors in women [ 10 ] or a lack of attention to early signs of disease in women and the absence of any special recommendation for screening programs [ 32 ]. In fact, we found an almost significant difference ( p = 0.063) in the current average age of males and women with a negative phenotype, with women who are yet to develop the disease being older.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, most pathogenic variants are limited to a small number of families or even specific individuals [ 9 ]. Therefore, the study of recently identified pathogenic variants with a founder effect that affect homogenous populations represents a great opportunity for the description of clinical phenotypes [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Description of a Cohort with a New Truncating MYBPC3 Variant for Hypertrophic Cardiomyopathy in Northern Spain

Suárez

Ubierna

Basas

et al. 2023

Genes

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Background: The pathogenicity of the different genetic variants causing hypertrophic cardiomyopathy (HCM) and the genotype/phenotype correlations are difficult to assess in clinical practice, as most mutations are unique or identified in non-informative families. Pathogenic variants in the sarcomeric gene MYBPC3 inherited with an autosomal dominant pattern, whereas incomplete and age-dependent penetrance are the most common causes of HCM. Methods: We describe the clinical characteristics of a new truncating MYBPC3 variant, p.Val931Glyfs*120, in 75 subjects from 18 different families from northern Spain with the p.Val931Glyfs*120 variant. Results: Our cohort allows us to estimate the penetrance and prognosis of this variant. The penetrance of the disease increases with age, whereas 50% of males in our sample developed HCM by the age of 36 years old, and 50% of women developed the disease by the time they reached 48 years of age (p = 0.104). Men have more documented arrhythmias with potential risk of sudden death (p = 0.018), requiring implantation of cardioverter defibrillators (p = 0.024). Semi-professional/competitive sport among males is related to earlier onset of HCM (p = 0.004). Conclusions: The p.Val931Glyfs*120 truncating variant in MYBPC3 is associated with a moderate phenotype of HCM, with a high penetrance, onset in middle age, and a worse outcome in males due to higher risk of sudden death due to arrhythmias.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Description of a Cohort with a New Truncating MYBPC3 Variant for Hypertrophic Cardiomyopathy in Northern Spain

Suárez

Ubierna

Basas

et al. 2023

Genes

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“…The MYH7 studies were also heterogeneous, and penetrance ranged from ≈40% to 100% (Figure 3A). The mean age at HCM diagnosis in MYH7 carriers was 33 years (95% CI, [31][32][33][34][35]. In relatives carrying P/LP variants of TNNT2, the penetrance was 62% (95% CI, 44%-78%) at a mean age at diagnosis of 36 years (95% CI, 31-40), although the studies were heterogeneous, and penetrance ranged from 25% to 100% (Figure S2A).…”

Section: Cross-sectional Prevalence and Penetrance: Family And Clinic...mentioning

confidence: 99%

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy

Topriceanu,

Pereira,

Moon

et al. 2024

Circulation

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Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease, as penetrance (proportion of G+ who develop disease) is variable, age-dependent, and not reliably predicted. Methods: A systematic search of the literature was performed. We employed random effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere genes in two different contexts: clinically-based studies on patients and families with HCM versus population/community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. Results: 455 full text manuscripts were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in non-proband relatives carrying P/LP variants identified during cascade screening was 57% (95% confidence interval [CI] [52,63]) and the mean age of HCM diagnosis was 38 years (95% CI [36, 40]). Penetrance varied from ~32% for myosin light chain ( MYL3 ) to ~55% for myosin binding protein C ( MYBPC3 ), ~60% troponin T ( TNNT2 ) and troponin I ( TNNI3 ), and ~65% for myosin heavy chain ( MYH7 ). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population, but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower; approximatively 11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ~8 years of follow up, starting from a mean age of ~16 years. However, short-term gene-specific phenotypic conversion varied between ~12% for MYBPC3 to ~23% for MYH7 . Conclusions: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve understanding of true lifetime penetrance in families and in the community, and to identify drivers of the transition from subclinical to overt HCM.

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“…Thus, combining such readily accessible data with advanced molecular technologies has helped in identifying various diseases caused by changes in DNA sequences. Indeed, understanding such genetic defects and detecting them at early stages have steadily progressed ( Mendez et al, 2021 ; Yu et al, 2021 ). No less important is an understanding of conserved elements of the human genome in the context of disease etiology, as well as disease prevention and treatment ( Mooney et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs

et al. 2022

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Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal (MYBPC1), fast skeletal (MYBPC2) and cardiac (MYBPC3), can result in cardiac and skeletal myopathies. Nonetheless, their evolutionary pattern, pathogenicity and impact on MyBP-C protein structure remain to be elucidated. Therefore, the present study aimed to systematically assess the evolutionarily conserved and epigenetic patterns of MYBPC family mutations. Leveraging a machine learning (ML) approach, the Genome Aggregation Database (gnomAD) provided variants in MYBPC1, MYBPC2, and MYBPC3 genes. This was followed by an analysis with Ensembl’s variant effect predictor (VEP), resulting in the identification of 8,618, 3,871, and 3,071 variants in MYBPC1, MYBPC2, and MYBPC3, respectively. Missense variants comprised 61%–66% of total variants in which the third nucleotide positions in the codons were highly altered. Arginine was the most mutated amino acid, important because most disease-causing mutations in MyBP-C proteins are arginine in origin. Domains C5 and C6 of MyBP-C were found to be hotspots for most mutations in the MyBP-C family of proteins. A high percentage of truncated mutations in cMyBP-C cause cardiomyopathies. Arginine and glutamate were the top hits in fMyBP-C and cMyBP-C, respectively, and tryptophan and tyrosine were the most common among the three paralogs changing to premature stop codons and causing protein truncations at the carboxyl terminus. A heterogeneous epigenetic pattern was identified among the three MYBP-C paralogs. Overall, it was shown that databases using computational approaches can facilitate diagnosis and drug discovery to treat muscle disorders caused by MYBPC mutations.

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

Cited by 8 publications

References 33 publications

Description of a Cohort with a New Truncating MYBPC3 Variant for Hypertrophic Cardiomyopathy in Northern Spain

Description of a Cohort with a New Truncating MYBPC3 Variant for Hypertrophic Cardiomyopathy in Northern Spain

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy

Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs

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