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For many couples struggling with infertility, the most frustrating thing is that doctors being unable to explain why pregnancy is not happening despite medical intervention. A new Indian study now shows that newer genetic technology can finally bring clarity.
Published in Journal of Assisted Reproduction and Genetics this month, the study analysed between 2021 and 2024, as many as 247 Indian men with severe sperm problems.
The study has been conducted by FRIGE Institute of Human Genetics, Ahmedabad, in collaboration with ICMR. It is the largest and most systematic genetic study of male infertility conducted in India to date and one of the few globally to use advanced family-based genetic analysis.
Many people assume infertility is mostly a woman’s problem. However, researchers said that in reality, male factors are a major part of infertility. But finding the cause in men is often difficult, they said.
A man may look healthy, and routine blood tests may be normal, but when semen is analysed, they either have no sperm or have very low counts. Unfortunately, in most cases, the reason is unknown.
Most infertility clinics rely on standard genetic tests such as chromosome analysis and Y-chromosome testing. These tests detect only large genetic changes.
The study detected chromosomal abnormalities in only three men and Y-chromosome microdeletions in eight, said Dr Deepak Modi, a scientist at ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, who was a part of the study.
“This means such routine tests could explain infertility in only 11 out of 247 men. Hence, the vast majority of men were left without a clear reason for their condition,” Dr Modi stated.
To go beyond conventional tests, researchers used newer DNA sequencing technologies that examine infertility-related genes in far greater detail.
Targeted sequencing (smMIP-based) was performed on 120 men, and whole exome sequencing (WES), often involving the patient and both parents, was performed on 48.
These approaches increased the diagnostic yield by an additional six to eight per cent, leading to an overall confirmed genetic diagnosis in 19 out of 247 men, or about 1 in 13. Based on their data of the known and newly identified causes, they estimate that as many as one in eight to one in five infertile men may have an underlying genetic cause.
A key insight from the study was that most well-established male infertility genes work through recessive inheritance, where a man is affected only if he inherits faulty copies of a gene from both parents.
This is particularly relevant in India, where marriage within communities is more common, said Dr Jayesh Sheth, the chairman and co-founder of FRIGE Institute of Human Genetics, Ahmedabad, who was also a part of the study.
This matters for couples as genetic diagnosis is not just about naming a condition, but it changes real decisions.
Some men with CFTR mutations produce sperm normally, but the ducts carrying sperm are missing or blocked. Without genetic testing, this can remain undetected.
“When identified early, this helps doctors plan sperm retrieval and IVF more effectively. Also, the female partners need to be tested to assess the risks of cystic fibrosis to future children.
“Finally, couples can make informed choices about genetic counselling and pregnancy planning,” said Dr Harsh Sheth, the lead author of the study and head of Advanced Genomic Technologies Division, FRIGE Institute of Human Genetics.
The study also highlights an India-developed innovation.
The targeted sequencing method used by the team is based on a patented technology designed to detect multiple genetic abnormalities in a single test, saving time and money, said Dr Harsh Sheth, the inventor of the new technology.
By combining classical genetics with modern sequencing, the study provides a roadmap for how infertility evaluation in India can move from exclusion-based testing to precise molecular diagnosis.
For couples struggling with infertility, a genetic diagnosis can reduce years of repeated and inconclusive testing, guide realistic decisions about IVF and sperm retrieval, clarify risks for future children and male relatives and prevent avoidable emotional and financial burden.
“We emphasise that sequencing should complement and not replace the existing chromosome tests, ensuring a comprehensive and cost-effective diagnostic strategy,” said Dr Sheth.
