Novel genetic variants of sperm chromatin compaction regulators are associated with non-obstructive azoospermia in...

The genetic basis of idiopathic male infertility remains largely elusive and multifactorial. Sperm cells undergo distinct chromatin compaction during spermiogenesis, primarily driven by sperm-specific nuclear proteins-protamines (PRMs) and transition proteins (TNPs). Genetic variations in protamine clusters due to polymorphisms may contribute to male infertility. However, their impact on sperm DNA integrity and fertility outcomes across ethnic groups remains inconsistent and unclear. However, these gene variants have not been studied among the Indian men in the context of male infertility.

This case-control study include collection of blood samples from non-obstructive azoospermic men from Bengali speaking population of West Bengal, India followed by genotyping with Sanger's sequencing of PRM1, PRM2, TNP1 and TNP2 genes among 445 non-obstructive azoospermic individuals (negative for Y-chromosome microdeletions) and 375 fertile controls. Suitable statistical methods were used to examine variant association. Additionally, in silico analyses were employed to predict the potential deleterious effects of the identified variants.

A total of 15 variants were identified, of which 10 showed significant association with azoospermia among the cases. In silico analyses predicted five variants to be potentially deleterious to the gene's function or disease-causing: rs75245770C>A and the novel variant OQ266297C>A in PRM1; the novel variants OQ507618A>T and OQ557494G>T in PRM2; and rs11640138C>T in TNP2.

Variants in protamine gene cluster may contribute to an increased risk of azoospermia among men in Bengali population. The novel variants identified in this study hold potential as genetic markers for male infertility screening in routine assisted reproductive techniques (ART) practice.