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Infertility: Genetic mutations can be the basis of a "severe spermatogenic failure"

IIn 2015, scientists estimated that between 40 and 50% of infertility cases worldwide were due to a "male factor". This could mean several things: the shape of the sperm, the amount of sperm produced by a man or the traps that can be harmful to health. sperm on the way out of the body. But a new research that will be presented Sunday at the European conference on human genetics retraces the issue of male DNA itself.

Previous studies have already shown that men can inherit certain aspects of their parents' infertility. But this study, co-authored by Joris Veltman, Ph.D., director of the Institute of Genetic Medicine at Newcastle University, and Manon Oud, Ph.D. student at the Medical Center at the University of Newcastle, Radboud University, takes a different approach, focusing not on hereditary mutations, but on those that occur only in each individual – known as de novo mutations.

Veltman, whose conclusions have not yet been published in a newspaper, tells reverse that their findings present "a completely different way in which genetic mutations can cause infertility," noting that it is "the first time that a study on this topic is performed."

Veltman and Oud focused on men with "severe spermatogenic failure" – those who produced no viable sperm (called azoospermia) or only small amounts of viable sperm, about less than 5 million sperm per milliliter of ejaculate.

In their sample of 108 men with severe spermatogenic insufficiency, the team discovered 22 mutations that could explain the difficulty in conceiving. These mutations were present in infertile men, but do not their fertile parents.

number of male sperm
Veltman and Oud found 22 common de novo mutations in sterile men.

All in all, these men had models of de novo mutations that differ from their parents but appear to affect a similar group of genes related to sperm production and sterility.

When a spermatozoon and an egg combine, the embryo receives half of its DNA from the mother and the other half from his father. But it is also normal for the embryo to end up with a crowd of New mutations unique to this individual. "We now know that each person is born with about 100 new mutations that are not present in his parent's genome," says Veltman.

Veltman and Oud estimate that the 22 de novo mutations identified in their study could be at the basis of the "severe spermatogenic failure" of their participants as they occurred in the genes involved in sperm production. In particular, they report two genes that caused serious mutations: TOPAZ1 and ODF1. Mutations within these genes are "likely to disrupt the normal functioning of genes," they write.

This is the beginning of this research, and the authors note in their presentation summary that the results will have to be reproduced. Currently, they are testing fruit flies (which, for now, have an impressive size of sperm) to gather more evidence that the de novo mutations they identified are related to male infertility. Ultimately, knowing the mutations to look for could help predict the effectiveness of Assisted Reproductive Technology for an individual and determine who might need to look at the options more seriously.

The prospect of de novo mutation could be very enlightening for men suffering from severe infertility. However, this alone can not fully explain the wider trends observed in the world for sperm health.

Researchers reported in 2017 that the number of sperm decreased by nearly 50% among men in North America, Europe, Australia and New Zealand. Genetics probably play an important role, but many other factors could lead to a drop in sperm. to count more globally. They include but are not limited to exposure to synthetic chemicals, obesity and long-term stress. Overall, it's a complicated picture, says Veltman.

"In general, we know very little why men are sterile," he adds. "When it's infertility, the man is often overlooked and very few tests are done to find out about the underlying causes of his infertility."


Human reproduction is vital for our species, but global infertility affects 1 in 6 couples, half of which is explained by a male factor. Although thousands of genes are involved in spermatogenesis, the genetic causes of severe spermatogenic failure remain largely unknown. De novo mutations (DNM), which occur spontaneously in the germ line or postzygotic, are known to play an important role in early disorders with reduced physical condition. Here we report the first exome sequencing study to investigate the role of DNM in male infertility. We examined and sequenced 108 patients with azoospermia or severe oligozoospermia (<5 million sperm / ml) and their fertile parents. In total, we have identified and validated 92 protein-modifying DNMs, which show an enrichment of the boundaries of the protein network. In addition, we found enrichment of functional loss variants (LoFs) in genes that were extremely intolerant to LoF. In all MNDs, 22 are likely to disrupt normal gene function and are found in genes involved in sperm production, such as TOPAZ1 and ODF1. In a complementary manner, we detected de novo copy number variants in 2 patients affecting several genes involved in cell replication and gamete production. We are currently conducting replication studies in additional cohorts to identify mutated genes in a recurring manner. In addition, a detailed phenotypic re-evaluation of the patient's phenotype, immunofluorescence staining of the patient's material and genetic screens using Drosophila Melanogaster are underway to more confidently link genes affected by a DNM to infertility. male. Our data provide early indications that DNM could play an important role in severe male infertility.

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