Heart conditions are a leading causes of illness in Malaysia and sudden cardiac death (SCD) is responsible for most of the deaths from heart disease worldwide.
“In Western countries, SCD accounts for 20% of total deaths and 50% of cardiovascular deaths,” says consultant genetic pathologist and Sunway Medical Centre’s molecular genetics laboratory head Dr Roziana Ariffin.
“According to studies from different regions, it is estimated that SCD rates range from 50 to 100 per 100,000 in the general population, of which the proportion of young patients is higher.
“The major cause of SCD above the age of 45 is coronary artery disease, while rare inherited cardiac disorders are the primary cause for the younger generation.” Dr Roziana points out that understanding and identifying genetic factors that predispose to SCD is important to lower risk of death and to develop new treatment and prevention methods.
“However, research and studies on SCD and cardiomyopathies (chronic diseases of the heart muscles) are scarce in Malaysia.
“In 2007, a retrospective study on sports- related deaths from autopsy cases in Malaysia showed that cardiomyopathy was the fourth cause of sports-related deaths, which is also more common in males and those above 50.
“Meanwhile, the Chinese have the highest prevalence of sudden deaths – double as compared to Malays and Indians, according to this study” she says.
There are two types of inherited cardiac disorders: genetic heterogeneity refers to a single disorder caused by mutations in different genes that can lead to the same disease, while allelic heterogeneity describes different mutations within the same gene, causing the same disease.
Primary electrical disorders of the heart include Long-QT Syndrome, Short-QT Syndrome, Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Early Repolarisation Syndrome and Idiopathic Ventricular Fibrillation, among others.
These syndromes can be categorised by specific ECG abnormalities during conditions such as exercise, fever or when taking certain drugs.
“It is crucial for heart-related disorders to be detected soonest possible as death may occur at any time,” emphasises Dr Roziana.
In March 2015, a 12-year-old boy in a relay run collapsed and died while waiting for the baton to be passed to him.
“The boy was perfectly well. The post-mortem, done at Hospital Kuala Lipis, showed no abnormal features.
“The cardiovascular system did not show any gross abnormality or any congenital anomaly. His heart weighed 160g, coronary arteries were patent and no coronary artery anomaly was found. The myocardium was generally normal.
“However, through molecular genetic testing, the results indicated positive identification of CPVT,” says Dr Roziana.
She explains that CPVT is a highly malignant heritable arrhythmia syndrome characterised by exercise- and stress- induced ventricular tachycardia.
A family background check revealed that four out of six children, including the 12-year-old boy, had passed away at a young age.
“The baseline ECG is usually normal, so diagnosis is based on the occurrence of arrhythmia during exercise stress-testing or Holter recording.
“If left untreated, 30% of individuals with CPVT will die before the age of 40,” she says.
According to Dr Roziana, the classification of inherited cardiomyopathies are based on functional and morphological features, which includes hypertrophic cardiomyopathies, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy.
“The genes identified for these disorders encode desmosomal, sarcomeric, cytoskeletal, and nuclear envelope proteins,” she adds.
In another case, a 16-year-old boy was playing football at school in the evening and had a fall, but did not lose consciousness.
He had a second fall at home an hour-and-a-half later, lost consciousness and passed away.
Postmortem findings showed an enlarged heart weighing 295g, a right ventricle to left ventricle ratio of 1:4, and an enlarged spleen. These findings are consistent with dilated cardiomyopathy.
“Unfortunately, more often than not, cardiac arrest is the first event for these individuals who did not present any symptoms previously.
“As a result, genetic testing of susceptible individuals is crucial to prevent SCD, especially those with a family history of SCD.
“Although these individuals may not show any symptoms yet, by knowing that they harbour genetic mutations that confer higher risk for SCD will enable them to have early preventative strategies, such as medical and surgical interventions and lifestyle modifications,” says Dr Roziana, adding that careful evaluation of the family members’ heart conditions can increase the detection rate from 22% to 53%.
Next generation sequencing (NGS)
“Sudden cardiac arrest (SCA) is a leading cause of nontraumatic mortality and at least 25% of SCA events have a genetic component and can be classified as inherited cardiac conditions (ICCs).
“Up to 50% of the cases involving young patients remain unanswered after a thorough autopsy investigation.
“Understanding and identifying the genetic components are crucial to diagnose and determine the type of relevant therapies, which can prevent deaths, as well as unlock new treatments,” emphasises Dr Roziana.
She adds that the traditional genetic assays for ICCs profile only a few genes at a time, yet are expensive, tedious and very limited in scale and scope.
“Molecular autopsy may help identify the cause of death in a large percentage of cases remaining as negative after autopsy and NGS complements the autopsy.
“The NGS technology in diagnosis is capable of testing many genes at one time. It may increase diagnoses in genetically and clinically heterogeneous disorders.
“However, it poses a challenge in evaluating variants of unknown significance that may complicate the diagnostic process.
“Nevertheless, it provides greater insights into the spectrum of variations in our larger population.
“NGS is much more affordable, accurate and can generate comprehensive genetic profiling of genes related to ICCs,” she says, adding that Sunway Medical Centre provides diagnostic services with advanced technologies to perform molecular and genetic testing.