Four percent of the region's population -- some 60 million people -- carry the mutation, concludes the study, published in Nature Genetics.
Scientists have long suspected that India, Pakistan, Sri Lanka and probably Bangladesh carry an outsized share of the global burden of heart disease.
One recent study predicts that by the end of this year India alone will account for 60 percent of the world's heart-related problems, which can have both lifestyle and genetic origins.
The new research by an international team of 25 scientists and doctors from four countries provides a partial answer as to why this is so: an unexpectedly common defect in a gene, MYBPC3, that provides the blueprint for a certain kind of heart protein.
"The mutation leads to the formation of an abnormal protein," said the study's main architect, Kumarasamy Thangaraj of the Centre for Cellular and Molecular Biology in Hyderbad, India.
"Young people can degrade the abnormal protein and remain healthy, but as they get older it builds up and eventually results in the symptoms that we see."These include severe hypertension, an inflammation and weakening of the heart called cardiomyopathy, and death due to sudden cardiac arrest.
Thangaraj and colleagues first discovered the mutation -- the deletion of 25 bits of genetic code -- five years ago in two Indian families. But its significance only came to light with the new research.
In two separate clinical tests, researchers checked for the presence of the variant in 800 heart patients and 699 healthy individuals across India.
The link between the symptoms and the genetic defect "were almost off the scale," leaving no doubt that the mutation played a key role in causing heart disease.
Further tests in different parts of the country of 28 unrelated families carrying the mutation showed that more than 90 percent of the oldest members in each family had heart problems.
While virtually absent among peoples from other parts of the world, the deadly genetic variant is equally spread across most of India's regions, its social castes, as well as its language and religious groups.
In a follow-up sampling of more than 2,000 indigenous individuals from 26 countries across five continents, the telltale mutation showed up in Pakistan and Sri Lanka, with some presence in Malaysia and Indonesia, but nowhere else.
The findings raise a perplexing question: if the bit of missing genetic code is so harmful, how did it become so common? Why did it not die out over the course of evolution, as usually happens to maladapted genes?
"The harmful effects are felt mainly late in life after people have had their children, so the mutation is essentially invisible to natural selection," explained co-author Chris Tyler-Smith, a researcher at The Wellcome Trust Sanger Institute in Hinxton, England.
"When carriers have children, the genes remain in the population," he told AFP by phone.
While many diseases hit in old age, very few are caused by a single mutation.
"The only other example I can think of is Alzheimer's, where there is a variant that affects the very late-onset form of the disease," Tyler-Smith said.
The MYBPC3 variant, he added, probably accounts for no more than five percent of heart disease in India, but still affects tens of millions of people.
"The bad news is that many of these mutation carriers have no warning that they are in danger," said Perundurai Dhandapany of Madurai Kamaraj University in Madurai, India.
"But the good news is that we now know the impact of the mutation."
The researchers said the findings should lead to better screening to identify those at risk, and may ultimately pave the way for the development of new treatments.
An estimated 17 million people around the world die of cardiovascular diseases every year, particularly heart attacks and strokes.