Infertility is commonly defined as the inability of a couple to conceive after one year of regular, unprotected sexual intercourse.
A 2022 study reported that male factors are solely responsible for approximately 20% of infertility cases and is a contributing factor to 30-40% of cases overall. Despite this, accurate statistics on male infertility remain limited due to underreporting, cultural stigma, and regional disparities.1
Beyond lifestyle choices such as diet and stress, genetic factors can also play a crucial role in male infertility.
A recent study published in the Journal of Assisted Reproduction and Genetics3 has identified key genetic factors contributing to male infertility in India using advanced sequencing technologies. The study aimed to systematically investigate the genetic architecture of severe male infertility among Indian men, with a particular focus on chromosomal abnormalities and de novo genetic variants.
The research was conducted by Dr. Harsh Sheth, Dr. Pritti Priya, Dr. Jayesh Sheth, Prof. Joris Veltman, and colleagues from multiple institutions, including the FRIGE Institute of Human Genetics in Ahmedabad.
Led by Dr. Harsh Sheth, the lead author and head of the advanced genomic technologies division at the FRIGE Institute, the study enrolled 247 men diagnosed with severe quantitative and qualitative sperm abnormalities between 2021 and 2024. According to a LinkedIn post by Prof. Jayesh Sheth, Chairman at Foundation For Research In Genetics and Endocrinology:
First Indian study and second global one to identify genes for male infertility and developing new technology to study chrimosomal error, Y micro deletion single letter change in one assay called as smmip based NGS for male infertility and Genetic diversity of infertile males in India.
The researchers adopted a comprehensive diagnostic strategy that combined conventional testing methods with advanced sequencing technologies. DNA from infertile men was compared with that of their parents to identify genetic alterations present in affected individuals but not inherited, known as de novo variants.
Conventional diagnostic methods typically identify the cause of male infertility in only 4-5% of cases. The study demonstrated that advanced genetic sequencing could increase diagnostic detection by an additional 6-8%. Dr. Sheth noted that the research was prompted by growing concerns over the rising prevalence of male infertility in India over recent decades.
All 247 participants underwent standard karyotyping and Y-chromosome microdeletion testing using STS-PCR. In addition, 120 patients received targeted genetic sequencing through an indigenously developed, patent-protected smMIP (single-molecule molecular inversion probes) assay covering 39 genes associated with male infertility.
A subset of 48 patients underwent whole exome sequencing (WES) using duo- or trio-based analysis, allowing researchers to study inheritance patterns and identify de novo variants with greater precision.
The study achieved an overall diagnostic yield of 7.7% (19 out of 247 patients).
Sequencing-based approaches contributed an additional 6-8% diagnostic yield beyond conventional testing methods.
Mutations were identified in several genes critical to male reproductive function:
PMFBP1 (Polyamine Modulated Factor 1 Binding Protein 1), DNAH1, and AR: These genes play essential roles in sperm production, morphology, and motility.
CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene: The study established a link between certain CFTR gene variants and male infertility. While cystic fibrosis typically develops when an individual inherits two highly disruptive CFTR mutations, leading to lung and pancreatic disease. The study found that men with a single mildly disruptive mutation may remain otherwise healthy. However, these individuals often have obstructed reproductive ducts, resulting in blocked sperm transport and infertility despite normal sperm production.
The researchers emphasized that genetic diagnosis enables clinicians to tailor treatment strategies more effectively, rather than proceeding directly to repeated assisted reproductive technology (ART) cycles without understanding the underlying cause.
1. Leslie SW, Soon-Sutton TL, Khan MAB. Male Infertility. [Updated 2024 Feb 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562258/
3. Sheth H, Priya P, Mishra V, Kale S, Ajagekar M, Dhondekar T, Desai M, Modi D, Colaco S, Banker M, Patel A, Bhanushali N, Shah T, Jasani P, Puvar A, Alobaidi BK, Sheth F, Sheth J, Veltman JA. Genetic diversity of infertile males in India. J Assist Reprod Genet. 2026 Jan 3. doi: 10.1007/s10815-025-03789-8. Epub ahead of print. PMID: 41483127.
(Rh/VK)