Globally, 7% of men are diagnosed with infertility, and for approximately half of these men a causal diagnosis is unknown. We hypothesise that at least 50% of these have a genetic element of causation, and that these genetic causes will be primarily comprised of single gene mutations. To identify such monogenic causes, we performed whole exome sequencing on 185 men diagnosed with azoospermia or severe oligozoospermia and their parents. This trio-based analysis allowed us to investigate both homozygous and compound heterozygous causes of disease.
Sequencing data was aligned to the reference genome and variants were annotated with their predicted effect on protein product, allele frequency in gnomAD and their predicted pathogenicity. Variant were prioritised based on their expression in the testis, published functional data, whether they interacted with known fertility genes, and whether orthologs were known to cause a mouse fertility phenotype.
We identified 62 predicted pathogenic recessively inherited bi-allelic variants, affecting 62 protein-encoding genes. Six of these bi-allelic variants were in genes already known to cause human male infertility; however, the clinical presentation was different from reported previously for 5 of the patients affected. The other 56 bi-allelic variants affected genes not previously associated with human male infertility. To explore functional links between the identified genes, we used the STRING database to illustrate protein-protein interactions between candidate infertility genes and found that genes involved in DNA repair and piRNA biogenesis were enriched within our cohort.
Together these results add evidence to the emerging role for monogenic mutations in male infertility. Providing patients with a molecular diagnosis will allow for a greater clarity of genetic counselling, including expected consequences of ART, for both reproductive outcomes and offspring health. This research is expected to lead to a shift in clinical practice towards genome sequencing for diagnostics.