# Project 1 - Deciphering the Molecular Drivers of Rare Forms of Human Infertility Using Integrative Genomic, Cellular, and Phenomic Approaches

> **NIH NIH P50** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $418,181

## Abstract

PROJECT ABSTRACT
Infertility affects up to 13% of childless couples yet the biological mechanisms underlying infertility and the effects
of infertility on overall health remains poorly understood. The goal of Project 1 within The Massachusetts General
Hospital Harvard Center for Reproductive Medicine will be to apply human genomics, transcriptomics and
phenomics to understand the mechanistic biological drivers of rare disorders of human infertility. A pervasive
methodologic theme of 'omics’ technologies runs through Project 1’s three specific aims. In Aim 1, infertility will
be viewed through the prism of rare hypogonadotropic and hypergonadotropic conditions that cause infertility.
Clinical investigators will apply contemporary genomic techniques to define the underlying genetic architecture
of infertility and to identify master regulatory pathways and networks that determine fertility. Three unique clinical
cohorts will be utilized to achieve this aim: US-based admixed cohorts of patients with idiopathic
hypogonadotropic hypogonadism (IHH)/Kallmann Syndrome [Massachusetts General Hospital] and primary
ovarian insufficiency [University of Utah]; and, a Saudi Arabia-based consanguineous cohort of patients with a
spectrum of rare Mendelian forms of infertility. The full spectrum of genetic variation (coding and non-coding
single nucleotide variants, insertion/deletion variants and structural variants) that confer substantial relative risk
for infertility will be determined and causal genes identified will be coalesced into common, final pathways
elucidating the predominant drivers of rare forms of infertility. In Aim 2, genetic variants identified from Aim 1 and
variants identified in Project 2 of the Center that relate to hypothalamic-hypogonadotropic forms of infertility will
be validated in CRISPR-engineered GnRH neurons derived from induced pluripotent stem cells generated by
the Genomics & Functional Core of the Center. Specifically, the cellular and molecular consequences of genetic
variation on GnRH neurons will be defined by comparing and contrasting the GnRH transcriptome, morphology,
migratory capability and secretory function between wild-type and edited GnRH neurons. Similarly, genetic
variants relating to hypergonadotropic forms of infertility leading to primary ovarian insufficiency will be studied
in a Drosophila model system by ovary-specific RNAi knockdown (or overexpression) experiments. Finally, in
Aim 3, a hospital-based human biobank (Partners Biobank) will be utilized to perform a recall-by-genotype based
targeted phenotypic evaluation in individuals harboring pathogenic variants in infertility-associated genes. The
full reproductive phenotype (“reproductome”) will be defined using deep phenotyping studies that will define the
effects of harboring genetic risk variants on GnRH-induced pituitary LH pulse profiles and hypothalamic-pituitary
responsiveness to exogenous kisspeptin administration. Through these coordinated studies...

## Key facts

- **NIH application ID:** 10463545
- **Project number:** 5P50HD104224-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephanie Beth Seminara
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,181
- **Award type:** 5
- **Project period:** 2021-08-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463545

## Citation

> US National Institutes of Health, RePORTER application 10463545, Project 1 - Deciphering the Molecular Drivers of Rare Forms of Human Infertility Using Integrative Genomic, Cellular, and Phenomic Approaches (5P50HD104224-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10463545. Licensed CC0.

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