From molecular etiology to improved reproductive health for male infertility in Qatar (The FERTILITY-IQ Study)

Gametogenesis is necessary for the survival and propagation of virtually all organisms in the animal kingdom, and the genes and pathways governing its processes in both sexes are highly conserved. Spermatogenesis in particular, requires the coordinated activation of thousands of genes, and the complexity of its biological processes make it an exceptional model to dissect basic cellular functions relevant to organismal health and disease e.g. stem cell differentiation, DNA replication and repair, epigenetic control, small RNAs, ciliary biogenesis, etc. Many factors may impair spermatogenesis, and approximately 1 in 20 men are infertile, contributing to 15% of couples worldwide being unable to conceive. Infertility is also associated with lower quality of life, e.g. infertile men tend to die younger than their fertile counterparts, possibly due to defects in the aforementioned cellular processes. Further, among the subset of men who electively undergo surgical sperm retrieval for in vitro fertilization (IVF), 60% remain idiopathic, with no explanation or clear path for treatment. We hypothesize that a substantial fraction will harbor an as yet undiscovered genetic defect, based on two key observations: (1) while >500 genes are known to impair spermatogenesis in mouse, only ~80 have been discovered in humans, suggesting ample room for novel discoveries; and (2) the high prevalence of infertility despite the detrimental effect on reproductive fitness suggests that a high level of genetic heterogeneity underlies infertility, which makes identification by traditional diagnostic means challenging. We propose to pursue two strategies to bridge this diagnostic gap: (1) we will focus on men with familial forms of infertility (enriched in Qatar) where recessive founder mutations are shared by multiple males due to consanguinity; and (2) we will sequence very large sporadic cohorts of infertile men to find recurrent dominant (de novo) mutations implicating novel genes. Both strategies are underway – we have already sequenced >200 infertile Qatari men and their families, whereas our external collaborators have established the International Male Infertility Genomics Consortium comprising 6 centers and >2,500 patients so far. As such, this proposal is based on extensive preliminary data and a highly talented, multi-stakeholder team inside and outside Qatar. With adequate support, we aim to scale our biobank to create a national resource for Qatar, and join the consortium as high-impact global contributors to male infertility research. Importantly, in order to transform knowledge of etiology into translational medicine, we are planning extensive functional studies both in patient tissue and in model systems to investigate of molecular mechanism of pathophysiology. We anticipate these discoveries will facilitate the stratification of patients based on molecular subtypes, and with predicting course of action/treatment for certain patients based on genomic medicine. For example, to identify which men are more likely to successfully undergo surgical sperm retrieval and IVF versus those who may not benefit and may require alternative interventions. Understanding molecular etiology could therefore significantly improve patient management and lead to better psychological and health outcomes for our patients within the Qatari community, and for millions of men worldwide. In conclusion, we have assembled a team of experts with a proven track record to create a long-term resource for infertility studies in Qatar. Our specific aims are: Aim 1. To create a registry and biobank of infertile men as a long-term resource for research. Aim 2. To use genomic technologies to discover the molecular etiology underlying infertility. Aim 3. To use cellular and animal models to study biology and unravel treatment pathways. Altogether, we plan to biobank and sequence 400 patients with spermatogenic failure and their family members (where available), and to investigate the molecular mechanisms behind ~20 novel genes over the coming 3 years. To achieve this, we are contributing a sum of ~$400,000 in co-funding, for a total project value of $1m over 3 years. In doing this, we aim to greatly improve the field's understanding of the processes underlying normal male fertility, the epidemiology and causes of infertility in Qatar, and the consequences of mutations on quality of life. We also aim to create better diagnostic tools and prognostic indicators of reproductive health, and mentor graduate students and postdoctoral fellows to build a sustainable, knowledge-based economy around reproductive medicine in Qatar. Finally, as the study’s name suggests, the FERTILITY-IQ Program may launch a pilot national resource for male infertility, but eventually grow to include female infertility under the same long-term vision of improving reproductive health for all couples in Qatar.

Sidra Medicine