Scientists find two novel gene mutations that could explain overly muscular hearts in Asian populations, paving the way for early and accurate detection through precision medicine.
In the time of rising cardiac disease, who wouldn’t want a strong heart? But as the adage goes, too much of a good thing can also be bad. A heart that is too muscular has its own problems, such as in the case of the condition hypertrophic cardiomyopathy (HCM).
Affecting 1 in every 500 people, HCM is characterised by an overly muscular heart in the absence of other conditions like high blood pressure. In its earliest stages, HCM can be as innocuous as mild chest pain or shortness of breath. However, as the disease progresses and cardiac muscles become too thick, HCM can cause fainting or even sudden death due to a dangerously fast heart rhythm.
While heart muscles can thicken due to ageing or poor lifestyle habits, HCM is largely genetic condition and runs in families. Affected individuals have a one-in-two chance of passing the condition on to their offspring. Furthermore, when an individual is diagnosed with HCM, there is a 40 percent chance that an underlying genetic cause will be identified1 .
Genetic testing presents a potentially powerful way of catching HCM early by identifying those who are at risk of developing the disease. However, the literature around HCM is focused almost exclusively on Caucasian cohorts.
As a result, very little is known about the genetics of HCM in Asian populations although the disease is fairly common: a 2011 study2 examining over 18,000 young men conscripted into the Singapore Armed Forces revealed that five in every 1,000 of the men actually had HCM.
Variants understudied in Singaporeans
To gain a more ethnically comprehensive understanding of HCM, research scientists led by Professor Stuart Cook of Duke-National University of Singapore and Senior Consultant at the National Heart Centre, Singapore looked at the sequences of 15 known HCM-related genes in 224 Singaporean patients of mainly Chinese ancestry.
Their findings3, published in Circulation: Genomic and Precision Medicine, revealed that 60 percent of Singaporean patients diagnosed with HCM do not harbour the usual genetic mutations associated with the disease. When sequences were compared to a database of predominantly Caucasian HCM patients, the researchers saw that disease-causing genetic variants were much rarer in the Singaporean cohort.
In contrast, genetic variants of uncertain significance (VUS)—variants that have previously been documented but whose impacts have yet to be determined—were much more common, occurring in 24 percent of Singaporean patients, compared to only 7 percent of their Caucasian counterparts.
“A greater excess of VUS in Singapore HCM patients than in the Caucasian population was a clue suggesting that HCM genetics in Singapore is understudied,” explained study first author Dr Edmund Pua of the National Heart Research Institute Singapore, adding that such a high degree of uncertainty could negatively impact clinical management down the line.
“Variants classified as VUS in a genetic report remain inconclusive and cardiologists or genetic counsellors may be less confident when discussing patient management options related to them,” he said. “Patients receiving these inconclusive reports may find it difficult to understand and recall their results correctly, leading to false risk perception and greater patient distress.”
Aside from the predominance of VUS’s, Cook’s team also found two common genetic variants that were enriched in Singaporean-Chinese HCM patients.
The first variant, R79C, is caused by a change in the sequence of the TNNI3 gene involved in heart muscle contraction. Though reported in previous HCM studies, the variant was classified as benign as it was found in healthy individuals as well.
To explore the impact of R79C, the team recruited about 500 Singaporean-Chinese participants without HCM and subjected them to cardiac magnetic resonance imaging to produce detailed images of the heart. They found that despite being healthy, people with the R79C variant had larger, thicker-walled hearts than those without.
The second variant, R286H, is found on the TNNT2 gene, which works with TNNI3 to form thin filaments of the heart muscles. Cook’s study revealed that R286H was significantly enriched in people with HCM.
The team turned to lab experiments to determine R286H’s impact, comparing heart cells derived from induced pluripotent stem cells with and without the variant. Their results showed that the R268H mutation led to enlarged cell size, with mutant heart muscles needing more energy to function properly due to excessive contractions.
“Given the size of the Chinese population globally, both R79C and R286H could be associated with more than 200,000 cases of HCM,” said Pua, adding that they discovered both variants enriched in populations in China, Taiwan, Japan and South Korea.
According to Cook, while R79C and R286H are only two of several still-undescribed variants that could contribute to HCM in Asian patients, their identification lays the groundwork for a more holistic, ethnically-nuanced understanding of HCM.
“We hope to identify new causative genes that might be hidden in this understudied population using whole-exome sequencing in the near future,” he concluded.
1 Walsh, R., Buchan, R., Wilk, A.,John, S., Felkin, L. E., et al. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. European Heart Journal 38: 3461-3468 (2017)
2 Ng, C.T., Chee, T.S., Ling, L.F., Lee, Y.P., Ching, C.K., et al. Prevalence of hypertrophic cardiomyopathy on an electrocardiogram-based pre-participation screening programme in a young male South-East Asian population: results from the Singapore Armed Forces Electrocardiogram and Echocardiogram screening protocol. Europace 13:883-888 (2011)
3 Pua, C.J., Tham, N., Chin, C.W.L., Walsh, R., Khor, C.C. et al. Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients. Circ Genom Precis Med 13:e002823 (2020)