Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Ross, Samantha Barratt; Bagnall, Richard D.; Ingles, Jodie; Tintelen, J. Peter van; Semsarian, Christopher

doi:10.1161/circgenetics.116.001671

Cited by 21 publications

(9 citation statements)

References 34 publications

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“…In other well-established HCM genes 76% of variants were unique. 93 The corollary of the above is that if the VUS does not segregate with affected family members, the likelihood that the VUS is relevant for the family phenotype is reduced. However, this analysis must encompass the growing reality of bilineal or multivariant disease, which has been postulated to be more common in DCM 9,56 and ARVC.…”

Section: Positive Cascade Genetic Testing In An At-risk Family Membermentioning

confidence: 99%

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Hershberger

Givertz

et al. 2018

Genetics in Medicine

206

162

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Section: Positive Cascade Genetic Testing In An At-risk Family Membermentioning

confidence: 99%

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Hershberger

Givertz

et al. 2018

Genetics in Medicine

206

162

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“… 8 , 9 However, this approach needs to be used with caution as variants that are not very rare, including founder and recurrent variants, have been reported in HCM. 10 Previous studies identified 2 founder variants of MYBPC3 that are significantly enriched in HCM cases in South Asian 11 and Icelandic populations, 12 which are now mostly classified as pathogenic by clinical genetics laboratories in ClinVar despite being relatively common in specific populations. It is important to have a firm understanding of the genetic architecture of HCM in a given population, and to recognize population-specific alleles, including founder variants, before the ACMG/AMP framework can be confidently applied in that population.…”

mentioning

confidence: 99%

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Pua

Tham

Chin

et al. 2020

Circ: Genomic and Precision Medicine

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Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies. Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM ( TNNI3 :p.R79C, disease allele frequency (AF)=0.018; TNNT2 :p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls ( TNNI3 :p.R79C, Singaporean controls AF=0.0055, p=0.0057, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2 :p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA AF=0.0009, p<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance ( TNNI3 :p.R79C, 0.7%; TNNT2 :p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3 :p.R79C carriers had significantly thicker left ventricular walls compared to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3 :p.R79C is considered a VUS. Mutant TNNT2 :p.R286H iPSC-CMs show hypercontractility, increased metabolic requirements and cellular hypertrophy and the etiological fraction (0.93, 95% CI: 0.83-0.97) support the likely pathogenicity of TNNT2 :p.R286H. Conclusions - As compared to Caucasians, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-Caucasian populations.

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“…We observed a high rate of recurrent P (67.8%) and LP variants that were present in more than 2 unrelated subjects, results that are in line with those reported for large cohorts. 24,26,27 MYBPC3 and MYH7 are commonly reported as the 2 most prevalent HCM-related genes in Caucasian and some non-Caucasian populations. 26,28,29 The highest prevalence of MYBPC3 mutations observed in this study was consistent with previous reports.…”

Section: Discussionmentioning

confidence: 99%

Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy

Nguyen

Huynh³

et al. 2019

Circ J

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Background: Hypertrophic cardiomyopathy (HCM) is associated primarily with pathogenic mutations in sarcomeric genes. The aim of this study was to identify the prevalence and distribution of disease-causing mutations in HCM-associated genes and the genotypephenotype relationship in Vietnamese patients with HCM. Methods and Results: Genetic testing was performed by next-generation sequencing in 104 unrelated probands for 23 HCMrelated genes and in 57 family members for the mutation(s) detected. Clinical manifestations were recorded for genotype-phenotype correlation analysis. Mutation detection rate was 43.4%. Mutations in MYBPC3 accounted for 38.6%, followed by TPM1 (20.5%), MYH7 (18.2%), TNNT2 (9.1%), TNNI3 (4.5%) and MYL2 (2.3%). A mutation in GLA associated with Fabry disease was found in 1 patient. A mutation in TPM1 (c.842T>C, p.Met281Thr) was identified in 8 unrelated probands (18.2%) and 8 family members from 5 probands. Genotype-positive status related to MYH7, TPM1, and TNNT2 mutations was associated with severe clinical manifestations. MYH7-positive patients displayed worse prognosis compared with MYBPC3-positive patients. Interestingly, TPM1 c.842T>C mutation was associated with high penetrance and severe HCM phenotype. Conclusions: We report for the first time the prevalence of HCM-related gene variants in Vietnamese patients with HCM. MYH7, TPM1, and TNNT2 mutations were associated with unfavorable prognosis.

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Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Cited by 21 publications

References 34 publications

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy

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