Genetic Diversity of Infertile Males in India

India's largest male infertility genomics cohort found a genetic cause in just 7.7% of 247 men with severe sperm defects

Journal: Journal of Assisted Reproduction and Genetics | Published: 2026-01-03 | Type: Journal Article | PMID: 41483127 Authors: Sheth H et al. (FRIGE Institute of Human Genetics, Ahmedabad; ICMR-National Institute for Research in Reproductive and Child Health, Mumbai; Banker IVF, Ahmedabad) Funding/COI: Wellcome Trust, Gujarat State Biotechnology Mission, Department of Health Research Young Scientist Fellowship, Indian Council of Medical Research. COI not listed.

Summary

A prospective cohort of 247 Indian men with severe male infertility underwent karyotyping, Y-chromosome microdeletion testing, and — for subsets — targeted panel sequencing or whole exome sequencing (WES). Despite deploying the full toolkit of modern genomic diagnostics, a confirmed genetic cause was found in only 19 men (7.7%). The remaining 92.3% left without a molecular explanation. The authors argue this supports moving trio WES into the front-line workup; the data are more modest than that recommendation implies.

Claims

• Gonosomal aneuploidies (e.g., Klinefelter syndrome) found in 3/247 patients (1.2%; 95% CI 0.3–3.5%)
• Causal AZF microdeletions found in 8/247 (3.2%; 95% CI 1.4–6.3%)
• Targeted sequencing of 39 genes (n=120) identified pathogenic/likely pathogenic variants in 4/120 (3.3%; 95% CI 0.9–8.3%); CFTR variants found in 3 additional patients where phasing was not possible
• WES (n=48, duo/trio design) yielded pathogenic variants in 4/48 (8.3%; 95% CI 2.3–19.9%), hitting genes PMFBP1, DNAH1, and AR
• No de novo or copy number variants confirmed causative, though candidate genes were flagged
• Sequencing added approximately 6–8% diagnostic yield over guideline-standard tests alone
• Overall diagnostic rate across all methods: 7.7% (19/247; 95% CI 4.7–11.8%)

Study Quality

This is a prospective, multi-institution cohort study — the design is appropriate for the question. The use of duo/trio WES to confirm segregation and detect de novo variants is methodologically sound and a genuine strength over retrospective chart reviews. Confidence intervals are reported throughout, which is more than most papers in this space bother to do.

The study does not apply all tests to all patients, which complicates interpretation. WES was performed in only 48/247 participants, and targeted sequencing in 120/247. The criteria governing who received which test are not fully detailed in the available sections. That means the 8.3% WES yield is drawn from a selected subset — likely enriched for cases where simpler tests failed — and should not be extrapolated to all severe male infertility as if it were a random sample. The confidence interval for the WES yield (2.3–19.9%) reflects exactly this uncertainty.

Red Flags

• Subgroup selection bias: WES was applied to only 48/247 men; who qualified and why is unclear, likely inflating the WES yield figure
• Wide confidence intervals throughout: the WES diagnostic yield CI spans 2.3–19.9% — the true effect is poorly constrained at this sample size
• Strong recommendation, thin data: the conclusion that trio WES should be a "first-tier investigation" rests on 4 positive WES cases; that is a hypothesis-generating result, not practice-changing evidence
• COI not listed: an oversight or an absence — either way, it should be stated explicitly given IVF clinic co-authorship (Banker IVF)
• Single-region recruitment: patients recruited primarily in Ahmedabad; generalizability to India's genetic diversity is limited
• No de novo variants confirmed causative: the trio design was partly justified for de novo detection, yet none were confirmed — either truly rare or the cohort was underpowered

Strengths

• Largest published Indian cohort for this question (247 patients), filling a genuine gap in non-European male infertility genetics data
• Independent, non-industry funding (Wellcome Trust, ICMR)
• Trio/duo WES design is the right approach for segregation and de novo analysis
• Multi-modal testing (karyotype + AZF PCR + targeted panel + WES) allows direct comparison of diagnostic yields
• Proper CIs reported; no p-value theater

Verdict

A solid foundational dataset for Indian male infertility genetics, but its clinical conclusion outruns its evidence. The 7.7% overall diagnostic rate — with or without WES — means the overwhelming majority of severe male infertility cases remain genetically dark even with current state-of-the-art tools. That is the real finding here, and it is important: this is a disease where we are mostly guessing. The call to make trio WES a first-tier test is premature from 4 positive cases out of 48; a well-powered RCT or at minimum a much larger prospective cohort with consistent WES application is what the field actually needs. Worth reading for the data; read the conclusion with skepticism.