Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling

Ingles, Jodie; Doolan, Alessandra; Chiu, Christine L; Seidman, Jonathan G.; Semsarian, Christopher

doi:10.1136/jmg.2005.033886

Cited by 344 publications

(269 citation statements)

References 20 publications

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“…[5][6][7] A subset of HCM patients (5%) are found to harbor more than one pathogenic mutation (i.e., homozygous or compound heterozygous), which may confer a more severe form of disease with a higher incidence of adverse outcomes including heart failure and sudden death. [8][9][10] Genetic testing in HCM is part of routine clinical practice, and identification of a pathogenic mutation allows predictive genetic testing to be performed in at-risk relatives. Overall, the mutation detection rate for HCM genetic testing is 50-60%, although some variation exists in different cohorts.…”

Section: Introductionmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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Purpose: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Methods:Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current populationbased allele frequencies.Results: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Conclusion:Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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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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“…Recently, two or more sequence alterations present either in the same or in different genes were demonstrated to occur in 3-5% of cases of familial HCM, associated with a greater clinical severity of HCM. [6][7][8] Similarly, compound and digenic heterozygosity were identified in patients with arrhythmogenic right ventricular cardiomyopathy, whereby several desmosome and celljunction genes were found to carry more than one mutation likely associated with low penetrance. 9 It is to be expected that similar modifiers exist for DCM; even though a single case of a 14-year-old boy with manifestations of DCM and mutations in both MYH7 and TNNT2 has been published, 10 little is known about the genes and the molecular mechanisms involved in modifying the phenotype of familial DCM.…”

Section: Introductionmentioning

confidence: 99%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

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Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling

Cited by 344 publications

References 20 publications

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

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

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

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