Response by Ho et al to Letter Regarding Article, “Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)”

Ho, Carolyn Y.; Day, Sharlene M.; Ashley, Euan A.; Michels, Michelle; Pereira, Alexandre C.; Jacoby, Daniel; Lakdawala, Neal K.; Ware, James S.; Helms, Adam S.; Colan, Steven D.; Seidman, Christine E.; Olivotto, Iacopo; Investigators, SHaRe

doi:10.1161/circulationaha.118.039069

Cited by 198 publications

(400 citation statements)

References 5 publications

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“…In a recent study, it was reported that young age at diagnosis and the presence of a sarcomere mutation are associated with an adverse clinical outcome. 31…”

Section: Finhcm Outcome Studymentioning

confidence: 99%

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

et al. 2019

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Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes ( MYBPC3 , MYH7 , TPM1 , and MYL2 ). Previously reported mutations by our study group ( MYBPC3 ‐Gln1061Ter, MYH7 ‐Arg1053Gln, and TPM1 ‐Asp175Asn) and a fourth major mutation MYH7 ‐Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow‐up, annual all‐cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare ( n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266–91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098–1.363, P < 0.001) were independent predictors of HCM‐related mortality and life‐threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all‐cause or HCM‐related mortality between the two groups. Mortality due to HCM during 10 year follow‐up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM‐related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM‐related mutations in non‐sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM‐related deaths annually.

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“…In a recent study, it was reported that young age at diagnosis and the presence of a sarcomere mutation are associated with an adverse clinical outcome. 31…”

Section: Finhcm Outcome Studymentioning

confidence: 99%

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

et al. 2019

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“…We collected four additional sets of independent test data to further assess the CardioBoost performance, using variants reported as pathogenic in ClinVar and HGMD 19 (both databases of aggregated classified variants), a diagnostic laboratory referral series from the Oxford Molecular Genetics Laboratory (OMGL), and a large registry of HCM patients, SHaRe 20 . CardioBoost consistently achieved the highest TPRs: predicting the most pathogenic variants with over 90% certainty ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…First, we directly assessed the strength of the association between the specified disease and rare variants stratified by the different tools. We compared the proportions of rare missense variants in a cohort of 6,327 genetically-characterised patients with HCM, from the SHaRe registry 20 , with 138,632 reference samples from gnomAD v2.0 ( Table 3 ). We calculated the Odds Ratio (OR) of each sarcomere gene for all rare variants observed, and for variants stratified by CardioBoost, M-CAP, and REVEL after excluding variants seen in our training data.…”

Section: Resultsmentioning

confidence: 99%

“…As a further assessment independent of gold-standard classification, we tested the association of variants stratified by CardioBoost with clinical outcomes in the same cohort of patients. Patients with HCM who carry known pathogenic variants in genes encoding sarcomeric proteins have been shown to follow an adverse clinical course compared with “genotype-negative” individuals (no rare pathogenic variant or VUS in a sarcomere-encoding gene, and no other pathogenic variant identified) 20–22 , with a higher burden of adverse events. Patients carrying benign variants in HCM-associated genes would be expected to follow a similar trajectory to those genotype-negative patients.…”

Section: Resultsmentioning

confidence: 99%

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Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

Zhang

Walsh

Whiffin

et al. 2020

Preprint

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“…An array of cardiomyopathy genes, and other cardiac genes, harbored VUSs in these subjects, and MYBPC3 was noted as having the highest number of VUSs. MYBPC3 truncations are a common cause of hypertrophic cardiomyopathy (1,33), and the MYBPC3 VUSs were all missense, perhaps suggesting a distinct mode of action. In context of genetic testing for cardiomyopathies, variants of uncertain significance are typically returned and can sometimes be interpreted with further familial testing and segregation analysis (34,35).…”

Section: Variants Of Uncertain Significance and Echocardiographic Finmentioning

confidence: 99%

Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Pottinger¹,

Puckelwartz²,

Pesce

et al. 2019

Preprint

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Background: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results:We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed race/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic/likely pathogenic variants in cardiac actionable genes (2%) and found evidence for clinical correlates in the electronic health record. African ancestry participants had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size, corrected for body surface area, from approximately 400 biobank participants (1,723 patient years) correlated with genetic findings. The presence of one or more uncertain variants in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. Conclusions:These data indicate a subset of uncertain variants may confer risk and should not be considered benign.

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Response by Ho et al to Letter Regarding Article, “Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)”

Cited by 198 publications

References 5 publications

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

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