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Male Infertility Exome Sequencing Leads to New Diagnostic, Treatment Insights

NEW YORK – A team of researchers from France and Tunisia has used exome sequencing to help in detecting and treating a severe form of male infertility called non-obstructive azoospermia.

Their study, published in the American Journal of Human Genetics on Tuesday, uncovered more than a dozen genes that appear to contribute to the condition, which is marked by sperm-free ejaculate.

"The aim of this study is to improve the genetic diagnosis of NOA, by identifying new genes involved in human NOA, and to better assess the chances of successful sperm extraction according to the individual's genotype," senior author Pierre Ray, a researcher affiliated with Inserm, the French national institute of health and medical research, and the Grenoble Alpes University Hospital, and his colleagues wrote.

As part of their study, the investigators searched for suspicious mutations in protein-coding sequences from 96 unrelated Tunisian men diagnosed with idiopathic NOA who had undergone testicular sperm extraction, or TESE, the primary treatment option for the condition.

"In view of the extreme genetic heterogeneity of NOA and the increasing affordability of the technique, we believe that [whole-exome sequencing] should now be included in the panel of genetic techniques proposed to infertile men," the authors suggested.

With a bioinformatic approach that focused on 151 candidate genes, the team sifted through the dozens of homozygous variants and nearly 1,500 heterozygous variants identified in each participant on average. The analysis highlighted highly deleterious, likely causal alterations affecting one or both copies of 16 genes, including 10 known NOA contributors and half a dozen new genes: DDX25, HENMT1, MCMDC2, MSH5, REC8, and TDRKH.

The NOA-associated alterations turned up in 22 of the study's participants, the investigators reported, providing a "high-confidence" diagnosis in 18 cases and potential diagnoses involving missense alterations not identified in the past for another four men with NOA.

The team noted that some of the newly identified genes have been implicated in infertility in women or in knockout mouse models. The deleterious risk variants landed in genes linked to processes ranging from DNA repair or piwi pathway activity to meiotic cell division or post-meiotic processes.

Because failed sperm retrieval treatments in 12 participants with NOA coincided with the presence of alterations affecting meiotic genes, meanwhile, the authors suggested that "genetic diagnosis prior to TESE could help identify individuals with low or null chances of successful sperm retrieval and thus avoid unsuccessful surgeries."

"Our results indicate that a clinical diagnosis interpreted in light of other clinical arguments can provide a strong argument against TESE," they concluded.