New Delhi

Male factors contribute significantly to infertility among couples, but the underlying cause often remains unexplained using routine tests. A new Indian study has shown that advanced genetic technologies can help identify the reasons in a substantial number of such cases.

Published this month in the Journal of Assisted Reproduction and Genetics, the study analysed 247 Indian men with severe sperm abnormalities between 2021 and 2024. Conducted by the FRIGE Institute of Human Genetics, Ahmedabad, in collaboration with the Indian Council of Medical Research (ICMR), it is the largest and most systematic genetic study of male infertility undertaken in India so far.

Researchers said infertility is frequently perceived as a woman’s health issue, but male factors account for a large proportion of cases. However, identifying the cause in men is often difficult because many appear clinically healthy and have normal routine blood tests, despite having no sperm or extremely low sperm counts.

Most infertility clinics rely on standard genetic tests such as chromosome analysis and Y-chromosome microdeletion screening, which detect only large-scale genetic abnormalities.

The study found chromosomal abnormalities in only three men and Y-chromosome microdeletions in eight, explaining infertility in just 11 out of 247 cases, said Dr Deepak Modi, scientist at the ICMR–National Institute for Research in Reproductive and Child Health, Mumbai, and a co-author of the study.

“This means that with routine testing, the vast majority of men are left without a clear explanation for their condition,” Dr Modi said.

To improve diagnostic accuracy, the researchers employed advanced DNA sequencing techniques that analyse infertility-related genes in greater detail. Targeted sequencing was carried out in 120 men, while whole exome sequencing—often involving both parents—was conducted in 48 cases.

These approaches increased the diagnostic yield by an additional six to eight per cent, resulting in a confirmed genetic diagnosis in 19 men, or roughly one in 13. Based on both known and newly identified genetic causes, the researchers estimate that between one in eight and one in five infertile men may have an underlying genetic basis.

A key finding of the study was that many established male infertility genes follow recessive inheritance, meaning a man is affected only if he inherits faulty copies of a gene from both parents.

This has particular relevance in India, where marriages within communities are relatively common, said Dr Jayesh Sheth, chairman and co-founder of the FRIGE Institute and a co-author of the study.

Researchers stressed that genetic diagnosis can directly influence clinical decision-making. For instance, some men with mutations in the CFTR gene produce sperm normally but lack the ducts required to transport it, a condition that may go undetected without genetic testing.

“Early identification helps doctors plan sperm retrieval and IVF more effectively. It also allows testing of female partners to assess the risk of cystic fibrosis in future children,” said Dr Harsh Sheth, lead author of the study and head of the Advanced Genomic Technologies Division at FRIGE.

The study also highlights an India-developed innovation. The targeted sequencing method used is based on a patented technology designed to detect multiple genetic abnormalities in a single test, reducing time and cost, Dr Sheth said.

By integrating classical genetics with modern sequencing, the study offers a roadmap for shifting infertility evaluation in India from exclusion-based testing to precise molecular diagnosis.

For couples, researchers said, a genetic diagnosis can reduce years of inconclusive testing, guide realistic fertility treatment decisions, clarify risks for future children and relatives, and prevent unnecessary emotional and financial strain.

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“We emphasise that advanced sequencing should complement—not replace—existing chromosome tests to ensure a comprehensive and cost-effective diagnostic strategy,” Dr Sheth said.