Characterizing the genetic etiology of delayed puberty with integrative genomic techniques

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare congenital forms of infertility that prevent patients from entering puberty and lead to infertility in their adulthood, thus causing significant burden to affected children both physically and psychologically. The lack of gonadotrophin-releasing hormone (GnRH), the hormone secreted by GnRH neurons, is the cause of IHH and KS. Despite previous efforts to identify causal variants in IHH/KS through pedigree analyses and studies to explore the functional dysregulation in GnRH neurons, the genetic etiology of IHH/KS remains largely unexplained. To address this challenge, I will (1) define a complete spectrum of genomic variants, ranging from single nucleotide variants (SNVs) to large structural variation (SV), from whole genome sequencing (WGS) of the largest IHH/KS cohort assembled worldwide, and perform joint association of coding and non-coding variants using already established statistical methods to identify risk genes and regulatory elements; (2) examine the impact of loss of function (LoF) mutations of infertility associated genes on transcriptome dysregulation in GnRH neurons; and (3) examine the effect of genomic variants in a broader range of individuals affected by constitutional delayed puberty (CDP). The planned research incorporates statistical modeling of genomic variants in trio genomes and interpretation of transcriptome dysregulation from RNA sequences in GnRH neurons to gain insights into the genetic etiology of rare congenital infertility. To ensure success of the project, Dr. Michael Talkowski, Director of the Center for Genomic Medicine (CGM) at Mass General Hospital (MGH), Harvard Medical School (HMS) and the Broad Institute, will serve as the primary mentor. Drs. Stephanie Seminara, reproductive endocrinologist and Professor of Medicine at MGH and HMS, and Harrison Brand, Assistant Professor and Lead of the Broad SV Team, will provide additional guidance as co-mentors. Drs. Talkowski and Seminara are world leaders in computational genetics and reproductive biology, and Dr. Brand has led numerous studies interpreting SVs in disease genomes and recently successfully transitioned to an independent research faculty at MGH and HMS through a K99/R00 award. In addition to their complementary leadership, a team of advisory committee members at various career stages will provide scientific feedback and career development advice throughout the project. The abundance of resources, tools, and scientific and clinical expertise accessible through the CGM, MGH, and the Broad Institute form a highly collaborative environment ideally positioned to support my transition to independence. The research will extend my expertise to include cutting-edge techniques and provide the opportunity to learn about phenotypes associated with congenital and constitutional infertility disorders, how to apply statistical methods to identify causal genomic loci, and how to interpret deviations in transcriptome activity. With these skills, I will be able to functionally characterize genetic variation affecting reproductive disorders and be well- positioned to launch my own high-performing and innovative independent research program. Project Number: 4R00HD107222-03 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Xuefang Zhao | Institution: BROAD INSTITUTE, INC., CAMBRIDGE, MA | Award Amount: $746,999 | Activity Code: R00 | Study Section: NSS View on NIH RePORTER: https://reporter.nih.gov/project-details/4R00HD10722203