# Characterizing the genetic etiology of delayed puberty with integrative genomic techniques

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $135,886

## Abstract

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...

## Key facts

- **NIH application ID:** 10799655
- **Project number:** 5K99HD107222-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xuefang Zhao
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $135,886
- **Award type:** 5
- **Project period:** 2023-03-02 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799655

## Citation

> US National Institutes of Health, RePORTER application 10799655, Characterizing the genetic etiology of delayed puberty with integrative genomic techniques (5K99HD107222-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10799655. Licensed CC0.

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