👤 Caitlin R Semsarian

Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry. Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR). After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes. Show less

Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10 Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM. Show less

There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification. Show less

Studies over the last 30 years have identified hypertrophic cardiomyopathy (HCM) as predominantly an autosomal dominant disorder caused by disease-causing variants in genes encoding the sarcomere proteins critical for contractile function. The two most common disease genes implicated are the MYBPC3 and MYH7 genes, with disease-causing variants in these two genes accounting for 70-80% of all genotype-positive HCM patients. This increased knowledge of the genetic basis of HCM has heralded the era of precision medicine, with genetic testing leading to more improved and precise diagnosis, effective cascade genetic testing in at-risk family members, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Most recently, novel insights into genetic mechanisms have been elucidated, spanning non-Mendelian aetiologies, non-familial forms of HCM, and development of polygenic risk scores. These advances have laid the platform for exciting future endeavours such as newer gene therapy approaches in HCM, including gene replacement studies and genome editing approaches to ultimately cure disease. This brief review summarises the current role of genetic testing in HCM patients and families, and introduces some new mechanistic insights leading to the consideration of gene therapy approaches for HCM. Show less

Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk. Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ -1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity. Show less

Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine-based care of individuals with hypertrophic cardiomyopathy. Show less

Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could inhibit aberrant mRNA splicing in hiPSC-CMs. We derived hiPSC-CMs from patients with hypertrophic cardiomyopathy due to Transcriptome sequencing of hiPSC-CMs confirmed aberrant splicing in 2 people with previously identified Transcriptome sequencing of patient specific hiPSC-CMs solved a previously undiagnosed genetic cause of hypertrophic cardiomyopathy and may be a useful adjunct approach to genetic testing. Antisense oligonucleotide inhibition of cryptic exon splicing is a potential future personalized therapeutic option. Show less

Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis. Show less

Genetic heart disease is a common cause of sudden cardiac arrest (SCA) in the young and those without an ischaemic precipitant. Identifying a cause of SCA in these patients allows for targeted care and family screening. Current guidelines recommend limited, phenotype-guided genetic testing in SCA survivors where a specific genetic condition is suspected and genetic testing is not recommended in clinically-idiopathic SCA survivors. To investigate the diagnostic utility of broad, multi-phenotype genetic testing in clinically-idiopathic SCA survivors. Clinically-idiopathic SCA survivors underwent analysis of genes known to be associated with either cardiomyopathy or primary arrhythmia syndromes, following referral to a specialised genetic heart disease clinic in Sydney, Australia between 1997 and 2019. Comprehensive review of clinical records, investigations and re-appraisal of genetic data according to current variant classification criteria was performed. In total, 22% (n = 8/36) of clinically-idiopathic SCA survivors (mean age 36.9 ± 16.9 years, 61% male) had a disease-causing variant identified on broad genetic testing. Of these, 7 (88%) variants resided in cardiomyopathy-associated genes (ACTN2, DES, DSP, MYBPC3, MYH7, PKP2) despite structurally normal hearts or sub-diagnostic structural changes at the time of arrest, so-called "concealed cardiomyopathy". Only one SCA survivor had a variant identified in a channelopathy associated gene (SCN5A). Extended molecular analysis with multi-phenotype genetic testing can identify a "concealed cardiomyopathy", and increase the diagnosis rate for clinically-idiopathic SCA survivors. Show less

Pathogenic variants in Patients with hypertrophic cardiomyopathy and Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in Truncating variants account for 91% of Show less

Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations. A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource. Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association. The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families. Show less

Myocardial oxygenation is impaired in hypertrophic cardiomyopathy (HCM) patients with left ventricular hypertrophy (LVH), and possibly also in HCM gene carriers without LVH. Whether these oxygenation changes are also associated with abnormalities in diastolic function or left ventricular (LV) strain are unknown. We evaluated 60 subjects: 20 MYBPC3 gene positive patients with LVH (G+LVH+), 18 MYBPC3 gene positive without LVH (G+LVH-), 11 gene negative siblings (G-), and 11 normal controls (NC). All subjects underwent 2D transthoracic echocardiography and cardiovascular magnetic resonance imaging for assessment of ventricular volumes, mass, and myocardial oxygenation at rest and adenosine stress using the blood oxygen level dependent (BOLD) technique. Maximal septal thickness was 20 mm in the G+LVH+ group, vs. 9 mm for the G+LVH- group. As expected, the G+LVH+ group had a more blunted myocardial oxygenation response to stress when compared with the G+LVH- group (-5% ± 3% vs. 2% ± 4%, P < 0.05), G- siblings (-5% ± 3% vs. 11% ± 4%, P < 0.0001) and NC (-5% ± 3% vs. 15% ± 4%, P < 0.0001). A blunted BOLD response to stress was also seen in G+LVH- subjects when compared with gene negative siblings (2% ± 4% vs. 11% ± 4%, P < 0.05) and NC (15% ± 4%, P < 0.050). G+LVH+ patients exhibited abnormal diastolic function including lower E', higher E to E' ratio and greater left atrial area compared with the G+LVH- subjects who all had normal values for these indices. Myocardial deoxygenation during stress is observed in MYBPC3 HCM patients, even in the presence of normal LV diastolic function, LV global longitudinal strain, and LV wall thickness. Show less

MYBPC3 splicing errors are a common cause of hypertrophic cardiomyopathy (HCM). Variants affecting essential splice-site dinucleotides inhibit splicing, whereas the impact of variants at conserved flanking nucleotides is less clear. We evaluated the contribution of MYBPC3 splice-site variants in a large cohort of patients with HCM and assessed the impact on splicing with RNA analysis. Patients attending a specialized multidisciplinary clinic, with a clinical diagnosis of HCM and genetic testing of at least 46 cardiomyopathy-associated genes, were included. Patients with variants in MYBPC3 splice sites with in silico-predicted effects on splicing were selected. RNA was extracted from fresh venous blood or paraffin-embedded myocardial tissue of the patients, amplified, and sequenced. Variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. We found 29 rare MYBPC3 splice-site variants in 56 of 557 (10%) unrelated HCM probands. Three variants were not predicted to alter RNA splicing, and 13 essential splice dinucleotide, nonsense, and short insertion or deletion variants were not further assessed. RNA analysis was performed on 9 variants (c.654+5G>C, c.772G>A, c.821+3G>T, c.927-9G>A, c.1090G>A, c.1624G>A, c.1624+4A>T, c.3190+5G>A, and c.3491-3C>G), and RNA splicing errors were confirmed for 7. Four variants in 4 families resulted in clinically meaningful reclassifications. After RNA analysis, 4 of 56 (7%) families with MYBPC3 splice-site variants were reclassified from uncertain clinical significance to likely pathogenic. RNA analysis of splice-site variants can assist in understanding pathogenicity and increase the diagnostic yield of genetic testing in HCM. Show less

Hypertrophic cardiomyopathy is an inherited cardiomyopathy with a prevalence of up to 1 in 200, which can result in significant morbidity and mortality. An iPSC line was generated from peripheral blood mononuclear cells obtained from the whole blood of a 58-year-old male with hypertrophic cardiomyopathy who carries the heterozygous pathogenic myosin binding protein C mutation p.Arg502Trp. Induced pluripotent stem cells express pluripotency markers, demonstrate trilineage differentiation potential, and display a normal karyotype. This line is a useful resource for studying and modeling hypertrophic cardiomyopathy. Resource table. Show less

Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with >1000 causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events. Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development. Show less

The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers. HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. -0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (-0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982). Show less

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. 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 population-based allele frequencies. 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. 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. Show less

Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed. The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors. Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified. Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, and 57 years) who experienced sudden cardiac arrest but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and 1 died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited 1 mutation independently from each of his parents with HCM)-that is, double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations-as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event. These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, thereby predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors. Show less

The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease. Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype. Show less

Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular genetic disorder, and can result in heart failure and sudden death in the young. No mutation is identified in up to 50% of cases of HCM following comprehensive analysis of known causal genes, however standard methods overlook large deletions and duplications. The multiple ligation-dependent probe amplification method was used to screen for large deletions and duplications in the myosin-binding protein-C (MYBPC3) and cardiac troponin T (TNNT2) genes in patients with HCM. One novel 3 base pair deletion was identified in MYBPC3 in a severely affected patient; however this change was also found in an unaffected relative. No alterations in the TNNT2 gene were identified. In conclusion, large deletions and duplications do not appear to play a major role in the pathogenesis of HCM. Show less

1. Familial hypertrophic cardiomyopathy (FHC) is a primary cardiac disorder characterized by myocardial hypertrophy that demonstrates substantial diversity in both genetic causes and clinical manifestations. 2. Clinical heterogeneity can be explained by the causative gene (at least 13 have been identified to date), the position of the amino acid residue affected by a mutation within the protein (over 450 mutations have been reported to date) and modifying genetic and environmental factors. 3. Multiple mutations are found in up to 5% of human FHC cases, who typically present with a more severe phenotype compared with single-mutation carriers (i.e. earlier onset of disease, greater left ventricular hypertrophy and a higher incidence of sudden cardiac death events). 4. Multiple mutations usually involve MYH7, MYBPC3 and, to a lesser extent, TNNI2, reflecting the higher contribution of mutations in these genes to FHC. 5. Multiple-mutation mouse models appear to mimic the human multiple-mutation phenotype and, thus, will help improve our understanding of disease pathogenesis. The models provide a tool for future studies of disease mechanisms and signalling pathways in FHC and its sequelae (i.e. heart failure and sudden death), thereby allowing identification of novel targets for potential therapies and disease prevention strategies. Show less

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder. Show less