Project 1 Abstract Using the human disease model of Isolated GnRH Deficiency (IGD), ~35 genes that control human reproduction have been discovered, several from our Center. We now propose three new Specific Aims (SAs) to accelerate these new genes discovery efforts dramatically. SA #1 will select subsets of our IGD cohort of 2,000+ IGD patients who: a) share a second rare phenotype; or b) are from multiplex IGD families, and provide them facilitated access to our whole exome sequencing (WES) pipeline in which we can define new coding sequence mutations. SA #2 will then use novel statistical enrichment analysis that will allow novel gene discovery using WES in our full IGD cohort. Similarly, this aim will also employ novel copy number variation (CNV) analysis pipelines to identify the role of CNVs in IGD. Finally, SA #3 will utilize whole genome sequencing (WGS) combined with RNA sequencing in IGD patients who: a) harbor “balanced” chromosomal rearrangements; or b) are from multiplex families or trios whose WES/CNV analysis were negative in order to define the full range of structural and non-coding variation in our IGD patients. Taken together, this combination of contemporary approaches, unique populations, and advances in next generation (NGS) should provide us with a fuller understanding of the mendelian genes that control human reproduction.