Endocrine Abstracts

Male infertility affects 7% of the general population and in about 50% of cases the aetiology remains unknown. The routine genetic testing is based on karyotype analysis and the screening of Y chromosome deletions. For long time the role of the other sex chromosome, the X chromosome, in spermatogenesis remained largely unexplored. While both sex chromosomes are derived from a pair of autosomes around 300 million years ago, their current size and gene content differs dramatically. The X chromosome has remained relatively stable in magnitude with around 155 Mb, the Y chromosome decreased to around 55 Mb. The importance of the Y chromosome in male fitness is undeniable since it contains the SRY gene and other testis specific genes relevant to normal spermatogenesis. Although some earlier study predicted that the evolutionary history of the X chromosome indicates its potential specialization in male fitness, up to recently, only three genes (among them the androgen receptor gene) were considered candidate genes for male infertility. In order to provide a comprehensive picture on the role of the nearly 800 protein-coding genes on the X chromosome, we performed a large-scale screening in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. We identified a total of 55 novel genes not previously linked to male infertility. Among them 21 genes recurrently mutated and strongly associated with and 34 genes moderately associated with azoospermia/cryptozoospermia,. The most frequently affected prioritized gene, RBBP7, was found mutated in 10 men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, this multicentre study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia, contributing to the development of future diagnostic gene panels.