Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Abstract

Background-Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results-Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype-phenotype correlations were scarce. Conclusions-Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations. (Circ Cardiovasc

Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy

“…13 Furthermore, several studies have demonstrated that HCM patients carrying multiple pathogenic gene variants have poorer prognosis in terms of earlier disease onset, increased left ventricular hypertrophy, and increased frequency of heart failure and sudden cardiac death, when compared with those carrying a single mutation. 5,6,11,16 Thus, the present case supports previous claims that rare homozygous variants may aggravate the clinical severity of HCM. Our HCM patient with a homozygous missense variant in MYPBC3 needed a heart transplantation, while his brother who also has the variant in homozygosis and the clinical phenotype of HCM will require specific attention at follow-up as there is the possibility of more adverse manifestations of HCM later.…”

“…In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 variants cause severe neonatal cardiomyopathy, which leads to heart failure and death within the first year of life . Furthermore, several studies have demonstrated that HCM patients carrying multiple pathogenic gene variants have poorer prognosis in terms of earlier disease onset, increased left ventricular hypertrophy, and increased frequency of heart failure and sudden cardiac death, when compared with those carrying a single mutation . Thus, the present case supports previous claims that rare homozygous variants may aggravate the clinical severity of HCM.…”

“…The heterogeneous phenotypic expression of HCM has been related to its diverse genetic profile. In larger series, ~3–5% of adult HCM patients prove to be compound or double heterozygotes for two disease‐causing variants in the same or different sarcomeric protein genes . Although data are still limited, indications are that patients with more than one sarcomere genetic variant, either in a compound heterozygote state or as a homozygous variant, have a more profound clinical profile of HCM …”

“…In larger series,~3-5% of adult HCM patients prove to be compound or double heterozygotes for two diseasecausing variants in the same or different sarcomeric protein genes. [4][5][6][7] Although data are still limited, indications are that patients with more than one sarcomere genetic variant, either in a compound heterozygote state or as a homozygous variant, have a more profound clinical profile of HCM. 4,5,[8][9][10][11][12][13] Case report A 39-year-old man presented in 1998 with shortness of breath during exertion.…”

Béta-myozin nehézlánc- és miozinkötő C-fehérje gén kettős mutáció azonosítása malignus megjelenésű hipertrófiás cardiomyopathia hátterében

“…Munkánkban két patogén mutáció, MYH7 p.Arg719Gln és p.Ser593ProfsTer11-mutáció hordozását dött. A mindkét mutációt hordozó családtagban malig-Új generációs szekvenáláson alapuló adatok szerint mutáció pozitív HCM-populációban 3-19%-ig terjed, átlagban 8% (19). Kisszámú betegcsoportok vizsgálata és esettanulmányok alapján a multiplex mutációt hordozókban súlyosabb klinikai képet, pl.…”