Researchers from the King Faisal Specialist Hospital and Research Centre in Saudi Arabia used exome sequencing, a method for sequencing all the protein-coding regions of genes in a genome, to establish a genetic basis for infertility in male patients. It is hoped that a more complete understanding of the molecular biology behind male infertility, alongside greater application of genomic medicine, will lead to improvements in treatment and diagnosis.
‘Male factors account for nearly half of infertility cases…with nearly seven percent of the male population estimated to suffer from infertility’ the authors reported in the journal Genetics in Medicine. ‘However, current estimates of the contribution of genetics to male infertility (15 percent) suffer from the lack of comprehensive genomic analysis in large cohorts.’
From a non-selected sample of 285 infertile male patients, 69 (24.2 percent) were suspected of displaying a monogenic form of male infertility, meaning that it was caused by a defect in a single gene. Over 400 genes have already been associated with male infertility in mouse models, suggesting that that the monogenic contribution in humans has been significantly underestimated.
The current standard method for diagnosing the cause of male infertility involves screening for chromosomal aberrations, such as Y-chromosome micro-deletions too small to spot by karyotype. However, this technique has a low diagnostic yield, and aberrations were only identified in 30 (10.5 percent) of the patients included in the study.
Of the 285 patients included in the study, 237 presented with non-obstructive azoospermia – a failure to make sperm – resulting in no sperm in the ejaculate. The remaining 48 patients displayed severe oligospermia, characterised by a sperm count lower than one million sperm per millilitre. An identical number of fertile men were recruited to the study as controls.
‘The 33 candidate genes we identified in this study represents by far the largest number of male infertility genes discovered by a single study,’ Dr Fowzan Alkuraya, the principal clinical scientist behind the study told GenomeWeb. ‘There are only around 40 genes linked to non-obstructive azoospermia in humans. Thus, our study nearly doubles the genes linked to this phenotype.’
These candidate genes were also selected and verified based on known biological roles in male germ cell development, as well as from compatible mouse models. Three of these genes were deemed as having ‘strong evidence’ of a connection to male infertility in humans, based on evidence from mouse models, as well as displaying independent variants in multiple unrelated patients.
The scientists are hopeful that these results will encourage further research dissecting the molecular basis of male infertility, as well as the development of future therapies and methods to improve its diagnosis and management.