NEW YORK – In a large genomics study of male infertility, researchers have discovered 36 candidate variants in 33 genes that were not previously connected to the condition, opening the door for new diagnostic methods and treatments.
Reporting in Genetics in Medicine on Wednesday, researchers from King Faisal Specialist Hospital and Research Center in Saudi Arabia performed exome sequencing on male participants to demonstrate that aside from traditional approaches, genomic analyses are needed to identify male infertility, especially the monogenic forms.
"Male infertility is a common problem affecting 7 percent of the global male population and yet it remains poorly understood at the molecular level," Fowzan Alkuraya, principal clinical scientist and senior consultant at King Faisal Specialist Hospital and Research Center, said in an email. "We aimed in this study to investigate the yield of a 'genomics-first' approach to male infertility."
The study was the largest to date on the genomics of male infertility, according to Alkuraya. In total, 285 male patients with either non-obstructive azoospermia or severe oligospermia were enrolled in the study from King Faisal Specialist Hospital and Research Center. The age range of participants was 24 to 64 years (average 37.4). As a control for exome sequencing data, an additional 285 fertile male participants of the same ethnicity were studied. Of the experimental cohort, there were 127 familial cases, 237 patients had non-obstructive azoospermia, and 48 of the patients had severe oligospermia.
The study participants underwent exome sequencing, along with the standard practice of chromosomal analysis, revealing that 24 percent of the cohort had variants considered to be potentially involved in male infertility. These variants were either previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4 percent) or were unpublished novel candidates (37 patients; 12.9 percent).
While using the traditional approach of karyotype and Y chromosome microdeletion (YCM) analysis, about 10 percent of patients demonstrated evidence of chromosomal aberration associated with male infertility in humans. In addition, the researcher noted, the 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1(CCDC79), PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in the study cohort. The researchers also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans.
"The 33 candidate genes we identified in this study represents by far the largest number of male infertility genes discovered by a single study," said Alkuraya. "To put our study in perspective, there are only around 40 genes linked to non-obstructive azoospermia in humans. Thus, our study nearly doubles the genes linked to this phenotype."
Alkuraya further noted that even though novel genes have been identified in non-obstructive azoospermia or severe oligospermia, patients are not typically screened for variants in these genes, which leaves more than 90 percent of patients with no identifiable cause, underscoring the importance of molecular diagnosis.
The researchers hope this study will propel others to join their effort to uncover more about male infertility as well as spur the additional use of exome sequencing in male patients. In addition, expanding the use of genomic medicine in urology could lead to personalized diagnosis and improved management of infertile males.
Alkuraya said that King Faisal Specialist Hospital now also aims to adopt exome sequencing as a routine clinical test for all male infertility patients. "We also hope that our results will spur interest among colleagues to join our effort to investigate significantly larger cohorts of male infertility to gain deeper insights into the molecular underpinning of this important medical problem," he said.
And although none of the discoveries made in this study can be immediately translated into infertility therapies, this may change in the future as the biology of the genes is better understood, Alkuraya said. In addition, he noted, "one should not lose sight of the potential these gene discoveries hold for the design of novel male contraceptives. For example, when we find that [a] mutation of a gene encoding a sperm head-specific antigen causes male infertility and nothing else, this will be an excellent target for a neutralizing antibody that targets that antigen to effectively and safely block male fertility."