Exploratory Whole-Genome Profiling of Greek Men with Oligozoospermia: Identification of Candidate Variants, Genes, and Biological Pathways

Background/Objectives: Oligozoospermia is a common cause of male infertility, yet its genetic basis remains incompletely understood, particularly in underrepresented populations. This exploratory pooled-WGS study aimed to identify and prioritize candidate coding variants, genes, and biological pathways of potential relevance to oligozoospermia in Greek men. Methods: Whole-genome sequencing was performed on genomic DNA from Greek normozoospermic and oligozoospermic men. Variants detected in the oligozoospermic group but not in the normozoospermic group within the present dataset were prioritized according to predicted functional impact, population allele frequency, evolutionary conservation, and multiple in silico pathogenicity prediction tools. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING protein–protein interaction analyses were subsequently performed to investigate the biological significance of the prioritized genes. Results: A total of 717,374 variants were identified exclusively in oligozoospermic men. Following prioritization, 171 coding variants (54 high-impact and 117 moderate-impact) mapped to candidate genes of potential biological relevance to male infertility, including 22 variants not previously observed in the databases examined. Functional enrichment analyses consistently highlighted biological processes related to cytoskeletal organization, microtubule dynamics, axonemal assembly, and ciliary function. Several genes previously implicated in male infertility, including DNAH5, DNAH11, and DNAH12, were prioritized alongside promising candidate genes such as COL6A6 and LAPTM4B. Conclusions: This study provides one of the first whole-genome investigations of oligozoospermia in a Greek population and expands the limited genomic data available for Balkan populations. However, given the exploratory pooled-WGS design and limited cohort size, these findings should be considered hypothesis-generating and require validation in larger, individually sequenced cohorts.