Mutations reveal missing pieces in male infertility puzzle

“Despite being a relatively common problem for 7% of adult males, infertility has seen little change in the way it is approached in the clinic,” explains Alkuraya. Clinicians currently focus on a handful of well-known chromosomal abnormalities, but there has been little effort to screen more broadly for other mutations that contribute to normal development of healthy spermatozoa. This is surprising, given that previous studies have identified numerous genes that may play a decisive role in this developmental process.

Alkuraya and colleagues set out to perform an unbiased search for fertility-related genes. They performed DNA sequencing of the exome—the genome’s protein-coding sequences—on 285 men diagnosed with defective sperm production. Their data confirmed an important role for many genes identified in past studies. They also uncovered dozens of novel potential causative mutations, as well as evidence that defective spermatogenesis may be a primary outcome of several disease-causing mutations that were not previously linked to male fertility.

According to Dolores Lamb, director of the Center for Reproductive Genomics at Weill Cornell Medicine, this work opens the door to a more comprehensive clinical understanding of this condition. “In future, severe cases of male infertility will likely be diagnosed with a molecular panel aimed at a group of specific genes,” she says, but notes that further work will be needed to validate the impact of individual mutations and their abundance in the general population. Alkuraya hopes this study will spur additional genomic surveys in the reproductive health community, but also believes that the general value of genetic screening in this context is already clear. “We aim to adopt exome analysis as a routine clinical test in our centre for all male infertility patients,” he says.

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