Medical researchers looking for new genetic causes of male infertility

A study led by medical researchers of the University of Tartu aims to find currently unknown hereditary factors that affect testicular development and cause a severe disorder of spermatogenesis and testis descent.

Nearly 7% of men are infertile and 60% of these cases remain unexplained. Broadly speaking, the causes of male infertility can be divided into two: disorders in spermatogenesis (the development of sperms) and congenital genital or, more generally, urogenital developmental disorders, among which abnormal testis descent is the best known.

Maris Laan, Professor of Human Genetics at the University of Tartu, said that there are currently few known genetic causes of male infertility which would also be studied in clinical practice. She explained that men usually have X and Y chromosomes in their cells, while females have two X chromosomes. Some boys, however, are born with two X chromosomes and one Y chromosome. “In addition to the absence of normal spermatogenesis, such men also have general health problems due to low testosterone level. This so-called Klinefelter syndrome is quite common: it occurs in up to four in every thousand men but remains undiagnosed in more than half of the cases,” said Laan. Laan estimates that up to 4% of all the infertile men who come to andrologist’s appointment have the syndrome.

Another well-known genetic cause is the loss, multiplication or relocation of some of the genetic material during gametogenesis. “An estimated 2.5% of infertile men lack an important section of the Y chromosome and this prevents normal spermatogenesis. Genetic causes are also well known in the cases of congenital obstruction or malformation of the seminal duct, which affects 1–2% of infertile men. In such case, the sperms matured in the testicle are prevented from reaching their target, i.e. sperms cannot reach the penis and the ejaculate and thus the uterus,” Laan said and specified that most of these patients have a mutation in the gene called CFTR.

“Here, molecular diagnostics is crucial – families suffering from infertility can be helped by assisted reproduction technology, as the sperms are viable and mature. It should be noted that in some cases, defects in this gene can also cause other health problems, for instance in the lungs, pancreas and other organs. The most difficult scenario is childhood cystic fibrosis,” Laan said. She emphasised this is why the detection of the mutation by a genetic study is essential for the health of both the patient and the future child.

In recent years, knowledge of the hereditary causes of congenital urogenital developmental disorders has also improved considerably, so the relevant clinical guidelines can be expected to improve.

New project

As many of the genetic causes of male infertility, especially spermatogenesis disorders, are currently unknown, researchers of the human genetics research group of the University of Tartu are starting a research project “Mono- and digenic causes of male infertility in the exome sequencing era: novel genes, digenic inheritance, pleiotropic effects and clinical implications” led by Professor of Human Genetics Maris Laan. The project will be implemented together with the Andrology Centre of Tartu University Hospital under the coordination of Margus Punab, Professor in Andrology at the University of Tartu.

According to Laan, high-level clinical expertise, together with modern methodological competence in genetics, computer science and animal testing, allows us to expect that the project will lead to considerable new knowledge about the development and function of reproductive organs and the genetic causes of infertility in both men and women.

“The importance of this project for Estonia is multifaceted, starting from the genetic analysis of hundreds of patients to the potential of changing clinical practice by using the knowledge and opportunities of genetics in diagnostics, prognostics and research-based treatment decisions, benefitting general health,” Laan said. She concludes that a better understanding of the causes of male infertility will also promote clinical research to find novel non-invasive molecular targets for the treatment of spermatogenic disorders.

The research project “Mono- and digenic causes of male infertility in the exome sequencing era: novel genes, digenic inheritance, pleiotropic effects and clinical implications“ is funded by the Estonian Research Council.