Light shed on de novo mutations behind male infertility

Mutations in genes that are involved in sperm production have been highlighted as a potential cause of infertility in affected men.

De novo mutations are genetic changes which occur either in the gametes of the parents or in early embryo development and therefore are not present in the parents of the affected individual. A genetic study of men with low sperm counts or no sperm has identified 29 such mutations which could be the cause of their fertility problems. Researchers at Newcastle University and Radboud University Medical Centre, the Netherlands, have said this could provide answers for some of the approximately 40 percent of infertile men with an unknown cause.

'This is a real paradigm shift in our understanding of the causes of male infertility. Most genetic studies look at recessively inherited causes of infertility, whereby both parents are a carrier of a mutation in a gene, and infertility occurs when the son receives both mutated copies, resulting in problems with their fertility.' said Professor Joris Veltman, one of the study's senior authors and Dean of Newcastle University's Biosciences Institute. 'At present, we don't understand the underlying cause in the majority of infertile men, and this research will hopefully increase the percentage of men for whom we can provide answers'.

Researchers compared the exome data of 185 infertile men to the exome data from both their mother and father, using a technique called trio-based whole exome sequencing. The data revealed 192 rare de novo mutations, of which 145 had an effect on protein production. Of these, 29 had been linked to reproductive processes, such as sperm production, while for a further 50 it remains unclear if they are linked to reproduction.

One gene of particular interest identified in this study was RDM5, which has previously been shown to cause severe infertility in mice. In a further analysis of existing data sets of a different cohort of men, six different mutations affecting this RDM5 gene were identified in seven of 2506 infertile men in the cohort, and none were found in the 5784 fertile men in the cohort.

Most of the mutations identified in this study are thought to be autosomal dominant whereby only one copy of the affected gene is needed to cause infertility. Consequently, sons conceived using assisted reproductive technologies such as IVF using sperm from these men could have a 50 percent chance of inheriting their infertility.

Professor Veltman said: 'If we are able to obtain a genetic diagnosis, then we can start understanding better male infertility problems and why some infertile men still produce sperm that can be used successfully for assisted reproduction.

'With our information, and the research others are doing, we hope clinicians can improve counselling for couples and recommend what is the best course of action in order to conceive, either by proposing an appropriate medically-assisted procedure or in cases where none is suitable, provide appropriate alternatives.'