# Genetics of Male Infertility: Accelerating the pace of discovery

> **NIH NIH P50** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2024 · $1,711,713

## Abstract

Abstract: Overall
Azoospermia impacts 1% of men globally, which translates to 645,000 men between the ages of 20 and 50 in
the United States. It is estimated that genetic causes explain 50% of infertility. Improved knowledge about
the genetic basis of infertility and associated overall health comorbidities will aid in the counseling of
infertile couples; justify the development of diagnostic screens; and may lead to patient-specific
treatment options. In the current personalized medicine era with reduced cost whole genome sequencing and
facile genome editing technologies, it is feasible to discover genetic underpinnings of infertility and develop
targeted therapies. Project 1 will discover genetic variants in men with unexplained nonobstructive
azoospermia (NOA) to identify targets for development of clinical diagnostics or therapy. In addition, Project 1
assemble an international team of experts to develop criteria for review and interpretation of infertility-
associated variants to be included in ClinGen, which will facilitate inclusion in clinical diagnostic screens.
Project 2 will establish high throughput in vitro gametogenesis platforms and a 100% chimeric mouse strategy
for rapid validation of azoospermia-associated variants discovered in Project 1. Project 2 will also evaluate the
impact of epigenetic modifiers on primordial germ cell development. Project 3 will provide “gold standard”
reproductive phenotyping in mouse models with human NOA associated variants discovered in Project 1 and
validated in Project 2. In mouse models of NOA, Project 3 will test the safety and feasibility of Sertoli cell and
germ cell gene therapies. Results of all interlinked projects will help justify the use of whole genome
sequencing as a diagnostic screen for male infertility and inform the public dialogue on the risks and benefits of
gene therapy in and around the germline. Core A will provide administrative oversight and facilitate
communications and data exchange among projects and cores to ensure that this P50 program achieves an
impact that is greater than the sum of its parts. The Education-Outreach Core will maximize the public impact
of this P50 by developing Saturday Academy hands-on laboratory experiences in reproduction and genetics for
middle school and high school students in underserved communities in Pittsburgh, Portland and Ithaca. P50
trainees from all sites will also contribute teaching modules to The DataJam, a national nonprofit that runs
academic education programs and competitions to engage middle school, high school and community college
students in data analytics and critical thinking.

## Key facts

- **NIH application ID:** 10992989
- **Project number:** 2P50HD096723-06
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** Kyle Edwin Orwig
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,711,713
- **Award type:** 2
- **Project period:** 2019-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992989

## Citation

> US National Institutes of Health, RePORTER application 10992989, Genetics of Male Infertility: Accelerating the pace of discovery (2P50HD096723-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10992989. Licensed CC0.

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