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Preface
Two family stories
A 9-year-old apparently healthy girl died suddenly after a running test at school. Resuscitation was futile. On autopsy, the left ventricle was hypertrophied, compatible with hypertrophic cardiomyopathy (HCM). Genetic testing revealed a pathogenic p.Asp175Asn substitution in the α-tropomyosin gene (TPM1), which is the third most common HCM-causing mutation in Finland, accounting for about 6% of all cases. Subsequently, her father, two aunts and grandmother were diagnosed with HCM and the same disease-causing mutation. The father had several risk markers of sudden death, and implantable cardioverter defibrillator was recommended.
In another family, a woman in her 60s was hospitalised due to atrial fibrillation, and echocardiography showed left ventricular hypertrophy. On genetic testing, a rare mutation, p.Thr410Ala of the α-galactosidase A gene (GLA), which causes Fabry disease, was found. In cascade screening, five family members had the same mutation, and symptomatic mutation carriers were started with enzyme replacement therapy.
Why HCM is important: pros and cons of genetic testing in HCM
HCM is arguably the most common cause of sudden cardiac death in the young and athletes. It is the most common monogenic heart disease with mainly autosomal dominant mode of inheritance, with a prevalence of 0.2% in unselected populations.1 However, the prevalence of likely pathogenic sarcomere variants is substantially higher up to 0.6%. HCM is caused primarily by mutations in the genes encoding sarcomere proteins, but disease-causing mutations in non-sarcomeric genes have also been found.1–3 Next generation sequencing techniques including panels of cardiomyopathy-related genes are available in clinical practice at a reasonable price. Current European Society of Cardiology HCM guidelines recommend genetic testing in all patients with HCM.1 Genetic testing provides several advantages. Finding a pathogenic mutation in a patient with HCM confirms the diagnosis, defines the aetiology of the disease and is useful in the differential diagnosis of phenocopies, such as Fabry disease or hereditary transthyretin amyloidosis. Genetic diagnosis in the index patient is the starting point for cascade screening of the family. A single blood sample is required to investigate the relatives, and only individuals with a disease-causing mutation in genetic testing need evaluation and follow-up at the cardiology clinic. Current treatment choices are mostly based on clinical manifestation of the disease rather than genetic diagnosis. However, with the rapid development of targeted therapies, our view may change in the future. Intriguingly, trials on first-generation gene-specific treatments of HCM are currently in phase II.2 Mavacamten, which decreases contractility by inducing allosteric inhibition of cardiac myosin ATPase, has shown very promising preliminary results for the treatment of obstructive HCM caused by MYH7 mutations.2
Genetic testing does not always help clinical work. First, mutations in certain sarcomere genes, for example, in MYH7, may account for more severe disease, but generally genotype–phenotype correlations are modest. Phenotypic heterogeneity is typical, as the severity of the disease differs from no left ventricular hypertrophy to severe obstructive HCM among the carriers of the mutations of the same gene, or of the same mutation, even in the same family. Second, with an increasing use of the next generation sequencing, rare variants of unknown significance (VUS) are often identified, and uncertainty of the pathogenicity of the variants may complicate clinical decision making. Finally, with current genetic testing, the cause of the disease remains unknown in about 25% of patients with a family history of HCM, and if there is no family history this percentage is even higher.2
Current concept of the genetic basis of HCM: HCM, ‘the monogenic disease of sarcomere’
In studies including comprehensive panels of sarcomere and non-sarcomere genes, 30%–60% of patients with HCM have a pathogenic or likely pathogenic mutation in sarcomere protein genes.2 Disease-causing mutations locate in the MYBPC3 and MYH7 genes in over half of the cases, and in about 10% of cases in other six sarcomere genes: MYL2, MYL3, TPM1, TNNT2, TNNI3 or ACTC1.2 Pathogenic variants in the genes encoding other sarcomere-associated proteins or non-sarcomere proteins, including CSRP3, FHL1, PLN, ACTN2, CRYAB, FLNC, MYOZ2, MYH6, TNNCI, TRIM55 and TRIM63, are rare.2 Pathogenic variants in the genes related to metabolism, such as GLA, PRKAG2 and LAMP2, are identified in about 2% of patients with HCM.2 Patients with transthyretin (TTR) or amyloid light-chain (AL) amyloidosis, neuromuscular diseases, syndromes like Noonan, or mitochondrial gene defects may have HCM, but these diseases, together with inborn errors of metabolism, account for no more than 5%–10% of cases.1
More than 1000 rare pathogenic variants in aforementioned over 20 genes have been found in HCM families, probably reflecting high rate of de novo mutations.2 Genetic background of HCM varies not only between families but also between different countries. Founder mutations, most often in MYBPC3, may account for a considerable proportion of cases with HCM in populations with a history of genetic isolation or bottleneck.3 4 In the FinHCM study, 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.3 Four founder or frequent mutations, Gln1061Ter in MYBPC3, p.Arg1053Gln in MYH7, p.Asp175Asn in TPM1 and p.Val606Met in MYH7, accounted for 28.0% of cases but were absent or very rare in non-Finnish Europeans in the gnomAD database.3 Mutations in MYL2, PRKAG2 and GLA were found in one or two patients.3
What about the rest?
Recessive mode of inheritance
What is the aetiology of HCM in the rest of the patients? So far, we have considered HCM a monogenic disease inherited in an autosomal dominant mode, but in the current issue of Heart, Salazar-Mendiguchía et al 5 describe several families with an autosomal recessive form of HCM caused by homozygous or compound heterozygous mutations in TRIM63, which were absent in the control population and in the gnomAD database. The affected patients had rather severe cardiomyopathy characterised by concentric left ventricular hypertrophy and a high rate of left ventricular dysfunction.5 Although only 0.39% of the index cases with HCM harboured homozygous or compound heterozygous rare variants in TRIM63,5 autosomal recessive inheritance in HCM deserves further investigation.
Variants of unknown significance
VUS in cardiomyopathy-related sarcomere and non-sarcomere genes may also contribute to the unresolved genetics of HCM. In a large patient population of 2912 cases with HCM, the causative mutation was detected in 32% of the cases, and inconclusive results were found in 15% of the cases.6 An expanded panel of 51 genes identified only a very small number of additional pathogenic variants compared with the original panel of 11 genes.6 In the FinHCM study, in addition to pathogenic or likely pathogenic variants, 49 rare VUS favouring pathogenicity were identified in 31 genes in 20.4% of the cases.3 In most of these cases, no other likely pathogenic or causal variant for HCM was found. Furthermore, for 82 rare variants ClinVar classification was not available.3 Some of these VUS are likely to be actual disease-causing mutations, and further studies are needed to determine their causality.
Intronic variants
Deep intronic variants of the known HCM-causing genes may account for a considerable number of cases with HCM. So far, technologies to study the genetics of HCM have included Sanger sequencing, next generation sequencing techniques of targeted cardiomyopathy gene panels, or exome sequencing, which identify variants only in the coding regions of the genes. Whole genome sequencing, which identifies variants also in the non-coding intronic regions, has detected pathogenic deep intronic variants in MYBPC3 in 9% of patients with HCM and inconclusive prior genetic testing.7 In the FinHCM study, using a panel of 59 cardiomyopathy-related genes, we found four pathogenic or likely pathogenic intronic variants (±2–13 bases from exons) in MYBPC3,3 but whole genome sequencing was not available to detect deep intronic variants. Large-scale whole genome sequencing studies are needed to investigate the importance of intronic variants in the genetics of HCM.
Polygenic, epigenetic and non-genetic factors
Finally, HCM may not always be a monogenic disease. About half of the patients do not have a family history of HCM, and a pathogenic sarcomere or non-sarcomere mutation is usually not found. These patients have less severe cardiac hypertrophy and better prognosis compared with those with a sarcomere mutation.1 It has been suggested that in cardiomyopathies, like in long QT syndrome (LQTS) and hypercholesterolaemia, non-Mendelian complex inheritance may play a significant role.8 Polygenic burden of common modulatory and susceptibility variants might cause cardiomyopathy, or modulate the primary gene defect.8 So far, there are no data to confirm polygenic basis for HCM, as this kind of studies would require comprehensive genetic studies in large patient populations. Also epigenetic and non-genetic factors such as age, obesity and hypertension may modulate the cardiomyopathy phenotype,8 but again the definite proof about their role in HCM is still missing.
What is the next step?
Discovering the genetic basis of HCM has given us valuable information about the inheritance, pathogenesis and heterogeneity of the disease. In the future, genetic diagnosis will be even more important as targeted gene-specific therapies emerge. To solve the missing genetics of HCM, collaboration between different study groups, as well as between cardiologists and basic scientists, is required. We need updated genetic databases, large collaborative genetic studies using newest technologies, research on functional consequences of different mutations, studies on familial inheritance and phenotypic characteristics of the causative variants, and finally trials on new emerging therapies. It is time to work together—and think out of the box.
Footnotes
Contributors JK designed, wrote and edited the article.
Funding This study was funded by the Academy of Finland, Sydäntutkimussäätiö, Kuopion Yliopistollinen Sairaala.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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