Abstract
Background. In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases.
Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population.
Patients and methods. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened.
Results. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively.
Conclusion. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland.
Key messages
The screening of ten variants in MYH7, TPM1, and MYBPC3 previously found in eastern Finnish cohorts with hypertrophic cardiomyopathy (HCM) revealed a causative mutation in 32 of 306 (10.5%) patients of the nationwide FinHCM Study.
The MYH7-R1053Q mutation is the third most frequent mutation for HCM identified in the FinHCM Study population, accounting for 5.6% of cases of HCM.
Combining the present findings with our previous results, a causative mutations was identified in 28% of the FinHCM Study subjects.
Introduction
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease manifesting as myocardial hypertrophy with an increased risk of sudden cardiac death (SCD). More than 1,400 pathogenic or HCM-associated variants primarily in the genes encoding sarcomeric proteins have been reported (Citation1). A disease-causing mutation is identified in up to 60% of patients with HCM. Some patients may carry double, or even triple mutations (Citation2,Citation3). However, not all of the reported mutations are causative but may act as modifiers in the presence of other disease-causing mutation, or the variants may be neutral polymorphisms (Citation4–6). Although MYH7 and MYBPC3 are reportedly the major genes for HCM worldwide, variation in HCM-causing genes and mutations between different populations has been described (Citation1,Citation7,Citation8). However, only a few reports on genetic screening in HCM in country-specific populations have been published, with a variable number of patients and geographical cover (Citation7–20).
In our previous studies based on a small cohort of 35 unrelated adult patients with HCM from eastern Finland, we have found disease-related mutations in MYH7, TPM1, and MYBPC3 but not in the genes encoding troponin I, cardiac alpha-actin, troponin T, myosin regulatory and essential light chains, and troponin C (Citation5,Citation7,Citation21–24). Two frequent founder mutations, TPM1-D175N (Citation21) and MYBPC3-Q1061X (Citation5), were identified, accounting for 11% and 17% of all cases of HCM in the aforementioned cohort of 35 patients with HCM, respectively (Citation7). In addition, we found a MYH7 mutation in two patients, a previously identified pathogenic mutation R719W in one patient and her family, and a novel MYH7-N696S mutation in a single child not belonging to the original study group (Citation21). Three additional mutations in MYBPC3 (IVS5-2A-C, IVS14-13G-A, K811del) (Citation5) were found in single patients or families. Together, all these mutations accounted for 14 of 35 (40%) cases of HCM in eastern Finland (Citation7). Furthermore, two MYBPC3 missense variants (R326Q and V896M) previously reported as disease-causing mutations by other groups, but with equivocal significance in our cohort, were found in single families (Citation5). Finally, in the screening of a cohort of patients with dilated cardiomyopathy (DCM) from eastern Finland, a R1053Q mutation in MYH7, associated with either HCM or DCM phenotype, was found in a single family (Citation24).
In our previous screening of a nationwide cohort of 306 Finnish patients with HCM (FinHCM Study), consisting of adult unrelated study subjects from all over Finland, we have investigated the aforementioned founder mutations TPM1-D175N and MYBPC3-Q1061X, originally found in the eastern Finnish cohort. In the FinHCM Study, these founder mutations accounted for 6.5% and 11.4%, respectively, of all cases of HCM (Citation8). The aim of the present study was to screen additional causative and possibly HCM-related mutations in MYH7, TPM1, and MYBPC3, which were previously detected in a small cohorts of HCM patients from eastern Finland (see the paragraph above), in the FinHCM cohort of 306 patients.
Patients and methods
The study group consisted of 306 unrelated Finnish patients (185 men, 121 women) with HCM from all five University Hospitals and from several Central Hospitals in Finland, representing all geographical areas of Finland. Characteristics of the study population have been described in our previous article (Citation8). The patients are mostly of Finnish origin, with a mean age of 53 years and a mean maximal thickness of left ventricular wall of 20 mm.
Altogether, eight previously identified mutations found in HCM patients from eastern Finland (MYH7-R1053Q, MYH7-N696S, MYH7-R719W, MYBPC3-IVS5-2A-C, MYBPC3-IVS14-13G-A, MYBPC3-K811del, MYBPC3-R326Q, MYBPC3-V896M) were screened (Citation5,Citation21,Citation24–27). In addition, during the screening of TPM1-D175N in the FinHCM cohort by direct sequencing a novel variant in TPM1 (D175G) was found. Finally, the screening of MYBPC3-K811del by direct sequencing in the present study revealed a previously reported mutation MYBPC3-A851insT (Citation28). To include all HCM-related variants found in Finnish patients, these two mutations were also screened in the 306 patients of the present study.
The genetic analyses were performed as previously described (Citation8) using either the TaqMan Allelic Discrimination Assay (ABI PRISM 7000 Sequence Detection System, PE Applied Biosystems, Foster City, CA, USA; MYBPC3-IVS5-2A-C, MYBPC3-IVS14-13G-A, MYBPC3-R326Q, MYBPC3-V896M) or direct sequencing (ABI PRISM 3100 Genetic Analyzer, PE Applied Biosystems, Foster City, CA, USA; MYH7-R1053Q, MYH7-N696S, MYH7-R719W, TPM1-D175G, MYBPC3-K811del, MYBPC3-A851insT).
In the present study, the mutations TPM1-D175G and MYBPC3-A851insT were screened in a control population of 94 individuals. All other mutations investigated in the present study, except for MYH7-N696S and MYH7-R719W, have been screened in controls in our previous studies (Citation5,Citation24). Of all the mutations screened in controls, only MYBPC3-R326Q and MYBPC3-V896M have been found in controls (Citation5). In the present study, the pathogenicity of the missense variants was assessed in silico by calculating the Condel score for each variant using a web-based software (Citation29).
Statistical analyses were performed with the IBM SPSS Statistics 19.0 software (IBM, New York, NY, USA). The echocardiographic parameters in three groups with the most common HCM-causing mutations (MYH7-R1053Q, n = 17; TPM1-D175N, n = 20; MYBPC3-Q1061X, n = 35) were compared with the one-way ANOVA and the Bonferroni post hoc test. The continuous variables with a skewed distribution were logarithmically transformed (Citation8).
The local Ethics Committee of the Kuopio University Hospital approved the study. A written informed consent was obtained from each patient.
Results
Causative mutations
The results of the genetic screening are shown in . A HCM-causing mutation was found in 32 of 306 subjects (10.5%). Of three mutations of MYH7 (R1053Q, N696S, R719W) R1053Q was found in 17 of 306 patients, accounting for 5.6% of HCM cases. Two of the 17 patients were confirmed to be related. There were no differences in the maximal thickness of the left ventricular (LV) wall or the LV end-diastolic and end-systolic dimensions between the carriers of MYH7-R1053Q (n = 17), TPM1-D175N (n = 20), and MYBPC3-Q1061X (n = 35; data not shown). Nine of the 17 patients with MYH7-R1053Q were from eastern Finland (regions of Kuopio, Joensuu, and Kajaani), seven from the southern region of Helsinki, and one from the south-western area of Tampere. No carriers of N696S or R719W were found in the FinHCM cohort. The Condel analysis predicted that all of the three mutations R1053Q, N696S, and R719W were pathogenic.
Table I. Results of the genetic screening of the mutations in MYH7, TPM1, and MYBPC3 among the 306 patients of the FinHCM Study.
TPM1-D175G was found in one proband (0.3%). The mutation was also carried by one of two clinically unaffected children of the proband. The D175G variant was not found in 188 control chromosomes. The Condel analysis predicted the variant to be pathogenic.
Causative MYBPC3 mutations were found in 14 patients. The splice site mutations IVS5-2A-C and IVS14-13G-A were both found in two of 306 patients (0.7%), respectively, whereas the deletion mutation K811del was found in six patients (2.0%). MYBPC3-A851insT was found in four patients (1.3%). This variant was predicted to alter the reading frame of MYBPC3 resulting in a premature stop-codon at codon 884, and a truncated protein. MYBPC3-A851insT was not present in a control population of 188 chromosomes.
Variants of unknown significance
The missense variants R326Q and V896M in MYBPC3 were found in eight (2.6%) and 10 (3.3%) patients, respectively. The Condel analysis predicted both R326Q and V896M to be damaging to the structure of the encoded protein.
None of the 306 patients carried more than one definite disease-causing mutation. However, four patients with MYBPC3-R326Q or V896M carried another, more probable causative mutation. One patient was double heterozygous for MYBPC3-R326Q and MYH7-R1053Q, and another patient for MYBPC3-R326Q and MYBPC3-K811del. Two patients with MYBPC3-V896M were double heterozygous (MYBPC3-V896M and MYBPC3-Q1061X, MYBPC3-V896M and TPM1-D175N, respectively).
Discussion
Principal findings
In the present study we screened 10 variants from three genes (MYH7, TPM1, MYBPC3) in the nationwide FinHCM Study, including 306 unrelated Finnish patients with HCM. Of the 10 mutations screened, the MYH7-R1053Q was the most prevalent mutation found in 17 patients, accounting for 5.6% of all HCM cases in the FinHCM Study population. A causative mutation in MYH7, TPM1, or MYBPC3 was identified in 32 patients, accounting for 10.5% of all cases of HCM in the cohort. In addition, a MYBPC3 variant of uncertain significance, R326Q or V896M, was carried by 18 patients.
MYH7-R1053Q
In the present study, MYH7-R1053Q was the most common HCM-causing mutation, accounting for 5.6% of cases. Following MYBPC3-Q1061X and TPM1-D175N, MYH7-R1053Q is the third most common mutation encountered in Finnish patients with HCM (Citation8). The 17 carriers of MYH7-R1053Q were clustered in the eastern and southern parts of the country. Because of its high prevalence in Finnish patients with HCM and geographical clustering in Finland, it is likely that MYH7-R1053Q is a founder mutation similarly to TPM1-D175N and MYBPC3-Q1061X (Citation5,Citation7,Citation21). However, haplotype analysis would be needed to confirm this hypothesis. MYH7-R1053Q was recently reported as a HCM-associated mutation in a single patient of a French HCM cohort (Citation17). In our previous study the mutation was not found in 150 control subjects (Citation24). In the present study, the Condel score predicted R1053Q to be deleterious. Based on all the evidence, we consider MYH7-R1053Q a causative mutation. Although associated with end-stage HCM in our previous report (Citation24), in the present study there was no difference in LV dimensions or maximal thickness between patients with MYH7-R1053Q, TPM1-D175N, and MYBPC3-Q1061X. This finding, although based on a small number of patients, supports the more recent concept that the clinical phenotype of HCM is affected also by other factors apart from the disease-causing mutation (Citation1).
TPM1-D175G
TPM1-D175N is a well-recognized disease-causing mutation that is common in Finnish patients with HCM (Citation8,Citation21,Citation30,Citation31). In the present study, a novel missense mutation (D175G) affecting the same codon of TPM1 was found in a patient with HCM and in one of her two clinically unaffected children. No mutations other than TPM1-D175N have previously been reported at this codon. However, there are several previous reports of different pathogenic mutations occurring in the same codon of other HCM genes, for example MYH7-R719W (Citation25) and MYH7-R719Q (Citation32). Several functional studies have shown the pathogenic role of the D175N mutation (Citation33,Citation34) implying that another non-synonymous mutation altering the amino-acid at codon 175 might be harmful. TPM1-D175G was not found in control chromosomes, and the Condel analysis predicted the variant to be damaging, implying that TPM1-D175G is a disease-causing mutation.
Causative MYBPC3 mutations
Of the six MYBPC3 mutations screened in the present study, we consider all four mutations leading to truncated proteins (IVS5-2A-C, IVS14-13G-A, K811del, and A851insT) pathogenic. In contrast, missense mutations MYBPC3-R326Q and V896M are possibly not pathogenic, as discussed below.
The IVS5-2A-C mutation of MYBPC3 expected to result in a truncated protein has not been reported elsewhere and appears to be uncommon also in Finnish patients, being present in 0.7% of FinHCM cases. In our previous study, IVS5-2A-C co-segregated with HCM in a large pedigree and was absent in 111 control subjects (Citation5).
MYBPC3-IVS14-13G-A was also quite uncommon (0.7%) in the present study. Recently, it was reported as a disease-related mutation by two other groups (Citation35,Citation36). In our previous study, this variant was found in a single family showing partial co-segregation, and was not found in controls. MYBPC3-IVS14-13G-A is predicted to utilize a cryptic splice site, which causes a change in the reading frame and a premature stop-codon leading to a truncated protein. This hypothesis was previously confirmed by cDNA analysis (Citation5).
Also MYBPC3-K811del appears to be quite uncommon, as it was found in 2.0% and ∼3% of patients in our present and previous studies (Citation7). Since our initial report identifying MYBPC3-K811del in 2002 (Citation5) in a single patient and two unaffected relatives, but not in controls, it has been reported to be a disease-causing mutation (Citation28,Citation37–41). Due to four lysine repeats at codons 811-814 it is impossible to determine which one is deleted from the protein. Therefore, all deletions of a lysine at codons 811-814 represent the same variant originally reported by our group (Citation5).
The MYBPC3-A851insT mutation, present in 1.3% of cases in the present study, is expected to result in a truncated protein. In the present study A851insT was not found in 188 control chromosomes. The mutation has previously been reported by Van Driest et al. (Citation28). In their study the number of patients carrying this mutation was not specified, but it was considered disease-related because the mutation was absent in 400 reference alleles.
MYBPC3 variants of unknown significance
MYBPC3-R326Q was found in 2.6% of the subjects of the present study. MYBPC3-R326Q has previously been reported to be a disease-causing mutation (Citation26). In our previous study on HCM subjects from eastern Finland, R326Q was identified in a small family without definite co-segregation with HCM. The variant was more prevalent in controls than in the HCM cohort (7/111 versus 1/37) and, therefore, was not considered disease-causing (Citation5). Subsequently, R326Q has been reported as a disease-causing mutation (Citation9,Citation11,Citation12,Citation19), a polymorphism (Citation10,Citation14,Citation28,Citation42), and as a variant of uncertain significance (Citation43). In the early reports R326Q was considered a disease-related mutation since it was not found in controls. However, no definite co-segregation in large pedigrees has been shown in any of the studies. Recently, Andreasen et al. reported that among many other postulated HCM-related mutations, R326Q was over-represented (32/4265) in the general population including over 4,000 European Americans, casting doubt on whether it is a causal mutation (Citation6). Interestingly, R326Q has also been reported in patients with dilated cardiomyopathy, both as a disease-related mutation (Citation44) and a polymorphism (Citation45). In the present study the Condel score predicted R326Q to be harmful to the structure of the protein. However, this does not necessarily prove R326Q to be a causal mutation, but implies that this variant might modify the HCM phenotype. Our finding that some of the patients carrying the R326Q variant had another, more probable, disease-causing mutation supports the hypothesis that R326Q is not a causative HCM mutation.
MYBPC3-V896M was found in 3.3% of the cases in the present study. It was initially published as a disease-causing mutation among South African HCM patients (Citation27). In our previous study on HCM subjects from eastern Finland, V896M was more prevalent in controls than in HCM patients (5/111 versus 1/37). The mother of the proband carrying the V896M variant was homozygous for this substitution, and appeared clinically unaffected in the initial evaluation (Citation5), although she has recently shown mild LV hypertrophy in cardiac MRI. On the basis of our findings we considered the V896M substitution a neutral polymorphism (Citation5). Subsequent reports on V896M in relation to HCM are controversial, ranging from a disease-causing mutation (Citation19,Citation46) to a polymorphism (Citation9,Citation14,Citation28,Citation42). Similarly to R326Q, definite evidence of co-segregation of V896M with HCM in large pedigrees is lacking. In addition, V896M was more prevalent (40/4151 among European Americans) than expected in a general population in an exome sequencing project (Citation6). Finally, in some but not all patients of the present study V896M was accompanied by another, more probable, disease-causing mutation. Nevertheless, the Condel score suggested V896M to be pathogenic, and, therefore, it is possible that V896M might modify the HCM phenotype.
HCM-causing mutations in the FinHCM Study
The screening of the mutations in the present and in our previous study (Citation8) revealed a definite or probable genetic cause for HCM in 86 of 306 (28%) patients of the FinHCM Study, which is one of the largest national HCM cohorts in Europe published. In the recent reports from other European countries, large-scale screening (at least four genes, more than 100 HCM patients) has revealed a disease-related mutation in sarcomeric genes in approximately 30%–60% of patients (Citation9,Citation10,Citation13,Citation16,Citation17,Citation20,Citation47,Citation48).
According to our present and previous studies on the FinHCM Study population, MYBPC3 appears, so far, the most common disease gene in Finnish subjects with HCM (16%) , similarly to many other recent European reports with national HCM cohorts (Citation9–11,Citation14–17,Citation19). In contrast to studies from other countries, TPM1 appears the second most common disease gene in Finnish subjects with HCM (7%), followed by MYH7 (6%). However, comprehensive targeted sequencing is needed to find all the major HCM genes in Finland. In most European studies, a large number of private mutations and only few founder mutations are found. In contrast, the genetic profile of the FinHCM Study is unique, since the three most common mutations (MYBPC3-Q1061X, TPM1-D175N, MYH7-R1053Q) account for 23.5% of cases of HCM. This is explained by the founder effect, which is present not only in HCM, but also in many other genetic diseases in the Finnish population due to the particular population history of Finland (Citation49). A strong occurrence of a founder effect has been reported also in Dutch HCM patients. Three common MYBPC3 founder mutations accounted for 21% of all cases of HCM in the Netherlands (Citation18). In addition, founder mutations confirmed by haplotype analysis have also been reported in South African (Citation27), French (Citation9,Citation48), Japanese (Citation50), and Spanish (Citation51) patients with HCM.
Limitations of the study
Only the screening of mutations previously identified in patients with HCM from eastern Finland, and two additional variants found during the initial screening of FinHCM specimens, has been performed in the FinHCM Study, resulting in genetic diagnosis in 28% of study subjects. Consequently, a significant number of HCM-causing mutations in the Finnish population remain to be found. Without comprehensive next-generation screening of all known HCM genes it is not possible accurately to determine all the disease genes and mutations in Finland. Moreover, exome sequencing is needed to identify yet unknown HCM-causing genes.
Because no extensive genealogical studies were done in the present study, it is possible that some of the 306 index patients, in addition to the two reported, are related. This is true especially for the carriers of an identical mutation which may have arisen from a distant common ancestor. However, as the genetically isolated Finnish population originates from a relatively small group of ancestors, eventually the majority of the population shares a common genetic background (Citation49).
Conclusions
In conclusion, the screening of 10 mutations of MYH7, TPM1, and MYBPC3, previously identified in Finnish patients with HCM, revealed a causative mutation in 32 of 306 patients, accounting for 10.5% of all cases of HCM in a nationwide FinHCM Study. Based on our present and previous studies, and reports elsewhere, all of the mutations screened in the present study, except for MYBPC3-R326Q and V896M, were considered disease-causing mutations. In the present study, MYH7-R1053Q was the most common mutation with a prevalence of 5.6%. To date, MYH7-R1053Q is the third most common disease-causing mutation found in Finnish patients with HCM, following MYBPC3-Q1061X and TPM1-D175N, previously found in 11.4% and 6.5% of patients in the FinHCM cohort (Citation8). Thus, the routine screening of these three mutations may reveal the genetic cause of HCM in up to 23.5% of patients in Finland.
Acknowledgements
We thank Raija Miettinen, MSc, Teemu Kuulasmaa, MSc, Satu Nenonen, RN, Eila Ruotsalainen, RN, and Sini Weckström, RN, for the assistance in data collection.
Declaration of interest: The authors state no conflict of interest. This study was supported by the Academy of Finland, the Finnish Foundation for Cardiovascular Disease, and the Kuopio University Hospital (grants to Johanna Kuusisto). Tiina Heliö has received grants from the Finnish Foundation for Cardiovascular Research, Finnish Medical Foundation, the special governmental subsidy for health sciences research, the Helsinki University Central Hospital, and the Koskelo Foundation.
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