Mutations in Sarcomeric Genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in Patients With Hypertrophic Cardiomyopathy

García-Castro, Mónica; Coto, Eliécer; Reguero, Julián R.; Berrazueta, José R.; Álvarez, Victoria; Alonso, Belén; Sainz, Rocío; Martı́n, Marı́a; Morı́s, César

doi:10.1016/s1885-5857(09)71513-0

Cited by 41 publications

(62 citation statements)

References 36 publications

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“…Fifteen cohort studies 7,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] provided data on the percentage of double mutations out of genotype-positive patients in HCM cohorts ( Table 2). A panel including 8 to 10 genes was used for testing 33% of the patients included in these studies, 5 to 7 genes in 44%, and 2 to 4 genes in 23%.…”

Section: Cohort Studiesmentioning

confidence: 99%

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Fourey

Care

Siminovitch

et al. 2017

Circ Cardiovasc Genet

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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

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Section: Cohort Studiesmentioning

confidence: 99%

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Fourey

Care

Siminovitch

et al. 2017

Circ Cardiovasc Genet

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“…The presence of multiple sarcomere gene mutations (double or triple heterozygosity, compound heterozygosity or homozygosity) was associated with a younger age compared to a single mutation or to the absence of mutations in a single report 41. In contrast, some other publications have reported a non-significant association between age and the presence of sarcomere mutations 42 43 46 47…”

Section: Demographic Characteristics and Family Historymentioning

confidence: 86%

“…Some studies reported that patients with mutations in MYH7 present earlier than MYBPC3 mutation patients,19 47 52 but others have failed to show such a difference37 39 43 46 48 49 or even describe a younger age at diagnosis for patients with truncating mutations in MYBPC3 37…”

Section: Demographic Characteristics and Family Historymentioning

confidence: 99%

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

Lopes

Rahman

Elliott

2013

Heart

174

105

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“…In these adult cases, a more severe HCM phenotype is generally seen, characterized by an earlier age of onset around the second decade or during childhood (Table 2). 6,14,15,[20][21][22][23][24][25][26][27][28][29][30] In a recent study on sarcomeric protein gene variants in childhood-onset HCM, 6 out of 84 children (7%) had compound variants. 6 This suggests that a gene-dosage effect might be responsible for manifestations at a younger age.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

et al. 2014

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Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p. (Trp792fs) and c.2827C4T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C4T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n = 21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.

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Mutations in Sarcomeric Genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in Patients With Hypertrophic Cardiomyopathy

Cited by 41 publications

References 36 publications

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

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