research

Breakthrough in understanding the genetic cause of severe male infertility in India

Sequencing based technology is developing a new paradigm in understanding the cause and providing tailored reproductive options to men with infertility, data from a large cohort shows.

For many couples, infertility is one of the most difficult—and least talked about—health journeys. What is often missed is that male-factor infertility contributes to around half of infertility cases, yet a large proportion of men still leave the clinic without a clear explanation for why sperm count, motility, or morphology is severely affected.

At FRIGE’s Institute of Human Genetics (FRIGE-IHG) and Decipher DNA, Dr. Harsh Sheth and his team have recently completed one of India’s largest integrated genomic studies of severe male infertility. Our work-published in high coveted Journal of Assisted Reproduction and Genetics—shows that the genetic architecture of severe male infertility in Indian men is distinct in important ways, and that sequencing-based testing can meaningfully improve diagnosis beyond conventional investigations.

But this is not just a research story. It is also a clinical translation story: sequencing-based testing—particularly smMIP sequencing—has begun to change the diagnostic paradigm, and the test is now available at FRIGE-IHG.

What is “severe male infertility” and why do genes matter?

Severe male infertility usually refers to men with very low sperm counts, no sperm in the ejaculate (azoospermia), or severe defects in sperm movement and shape. In our cohort, the most common presentation was oligoasthenoteratozoospermia (OAT) (about half of patients), followed by azoospermia (about one-third).

When sperm production is profoundly impaired, genetics becomes a highly plausible explanation. Unlike infections or lifestyle factors, genetic causes can:

The challenge is that male infertility genetics is highly heterogeneous—there are many genes, many mechanisms, and many mutations that can contribute.

The older diagnostic pathway: valuable, but incomplete

Most clinical pathways begin with WHO recommended tests:

These tests remain essential, and they diagnosed a meaningful subset of men in our cohort. However, they still leave many men labelled as “idiopathic” or “unexplained”.

This is where sequencing is changing the landscape.

What did we do at FRIGE-IHG?

We enrolled 247 infertile men with severe sperm abnormalities into a structured, stepwise genetic work-up.

  1. First-tier testing for all: karyotype + AZF microdeletion testing

  2. Sequencing for those without a diagnosis, using a pragmatic clinic-friendly approach:

    • Targeted sequencing using single-molecule molecular inversion probes (smMIP) (120 patients)
    • Whole exome sequencing (WES), preferentially in duo/trio format when parents were available (48 patients)

This design reflects real-world practice: sometimes you can obtain parental samples (which improves interpretation), and sometimes you can’t. A workable clinical pathway needs both options.

What did we find?

Conventional tests still matter

In our cohort, first-tier testing detected:

Together, this produced a diagnostic yield of roughly 4.5% from karyotyping and AZF testing alone.

Sequencing explained a further ~6–8% cases

When sequencing was added:

Overall, the integrated approach increased diagnosis to about 7.7% (19/247)—a meaningful improvement in a condition where “no answer” is still the default in many settings.

How does sequencing change the paradigm?

Sequencing changes male infertility diagnostics in three important ways:

1) It expands from “a few tests” to “a true genetic evaluation”

Older pathways are designed to detect a handful of causes. Sequencing allows us to evaluate dozens of definitive, high-confidence male infertility genes in one assay.

Instead of asking “Is it Klinefelter?” or “Is it an AZF deletion?”, we can ask: Is there a monogenic cause that explains the phenotype and informs prognosis?

2) It makes autosomal recessive diagnoses more visible—especially relevant for India

A major insight from our work is that autosomal recessive causes appear prominent among robust male infertility genes. In practical terms, this means that many diagnoses require two pathogenic variants in the same gene, inherited one from each parent.

This is precisely why family-based sequencing (duo/trio) is so powerful: it helps confirm whether two variants are truly in trans (on opposite copies), which is often necessary for confident diagnosis and counselling.

In India, where many communities practice endogamy and some settings include consanguinity, recessive inheritance patterns can be especially relevant—and sequencing helps us detect them.

3) It supports a “sequencing-led ladder” of care

Our findings support a shift where sequencing is not an afterthought, but a core part of the diagnostic pathway for severe male infertility—used thoughtfully alongside karyotype and AZF testing.

Why smMIP sequencing is a game-changer

When people hear “sequencing,” they often think of exomes or whole genomes—powerful, but expensive and not always scalable. smMIP sequencing offers a different solution: a targeted, high-throughput sequencing method designed for clinical diagnostics.

What is smMIP sequencing (in simple terms)?

smMIPs are short, designed DNA probes that “capture” specific gene regions. After capture, those regions are sequenced deeply and accurately. Because the targets are known in advance, the method is:

In our study, the smMIP assay targeted a curated set of 39 male infertility genes, chosen based on strong gene–disease validity. The sequencing depth was high (on average ~200× per locus), enabling confident variant detection within the targeted regions. The assay is designed and validated by Decipher DNA together with research teams from University of Newcastle and University of Edinburgh in the UK.

Why does smMIP matter for India?

Because it helps answer the question: Can we offer sequencing-based diagnosis at scale, without making it unaffordable?

The key strengths of smMIP sequencing in a diagnostic setting are:

Importantly, karyotyping remains necessary for detecting balanced chromosomal rearrangements that sequencing may miss—but smMIP offers an accessible path to bring sequencing into routine infertility evaluation.

Is this important for India?

Yes—because male infertility is common, the emotional and financial burden is high, and a “diagnostic odyssey” helps no one.

Sequencing-based diagnosis can:

Most importantly, it moves the conversation from uncertainty to explanation.

Should I consider sequencing-based genetic testing?

Sequencing is not necessary for every fertility concern. But it is especially worth considering if you have:

A genetics team can help decide the best approach: targeted smMIP testing, family-based exome sequencing, or both—alongside standard karyotype and AZF testing.

smMIP sequencing for male infertility is now offered at FRIGE-IHG

Based on the evidence from this study and our clinical translation pathway, FRIGE-IHG now offers smMIP-based targeted sequencing for male infertility genes as part of our diagnostic services for men with severe sperm defects—integrated with conventional testing and with escalation to family-based WES when clinically appropriate and when parental samples are available.

If you would like to know whether sequencing is suitable in your situation, you can contact us to discuss testing pathways and genetic counselling.