The G263X MYBPC3 mutation is a common and low-penetrant mutation for hypertrophic cardiomyopathy in the region of Asturias (Northern Spain)

Reguero, Julián R.; Gómez, Juan; Martı́n, Marı́a; Flórez, Juan P.; Morı́s, César; Iglesias, Sara; Alonso, Belén; Álvarez, Victoria; Coto, Eliécer

doi:10.1016/j.ijcard.2013.06.085

Cited by 9 publications

(5 citation statements)

References 12 publications

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“…In agreement with most series [ 4 , 7 – 9 , 14 , 15 , 17 ], our study shows that MYBPC3 is the gene with a higher proportion of P/LP variants, followed by MYH7 . While MYH7 variants are almost exclusively missense (in our cohort all of them), MYBPC3 is characterized by a significant incidence of radical variants [ 3 , 4 ].…”

Section: Discussionsupporting

confidence: 92%

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

et al. 2017

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IntroductionHypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation.MethodsThree hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease.ResultsThe percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN.ConclusionsA small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.

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Section: Discussionsupporting

confidence: 92%

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

et al. 2017

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“…The predominant clinical presentation in our population is moderate HCM with septal predominance, limited obstruction, but a high percentage of arrhythmias. These characteristics are like those described for other variants in the MYBPC3 gene that lead to truncation of the protein [ 12 , 17 , 28 , 33 ].…”

Section: Discussionsupporting

confidence: 64%

“…Several studies have attempted to define the phenotype associated with the variant in question [ 12 ], and although the first papers initially pointed towards a later onset, less hypertrophy, and a better outcome [ 13 , 14 ], more recent studies indicate that they are no different from patients with variants in thick and thin filament genes [ 12 , 15 , 16 ]. The importance of establishing genotype-phenotype correlations lies in the fact that this would enable improved risk stratification and changes in the management of carriers [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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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“…In certain populations, however, founder mutations comprise a large part of detected mutations. To date HCM founder mutations have been identified in MYBPC3 , MYH7 and TPM1 genes, and reported in the Netherlands [ 14 ], Spain [ 15 ], South Africa [ 16 ], Finland [ 17 ], Italy [ 18 ], Japan [ 19 ], South Asia [ 20 ] and in the Amish population [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure

et al. 2018

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During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.

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The G263X MYBPC3 mutation is a common and low-penetrant mutation for hypertrophic cardiomyopathy in the region of Asturias (Northern Spain)

Cited by 9 publications

References 12 publications

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

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

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure

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