# Epigenetics and Genetics of Infertility and Associated Comorbidities

> **NIH NIH P50** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2021 · $348,146

## Abstract

PROJECT SUMMARY
Despite extensive knowledge of genes required for gametogenesis, the causes of most human infertilities are
unknown. It is thought that about half of cases have a genetic basis, but it remains problematic to definitively
identify the exact genetic lesion(s) that may be responsible in a given person, even with genome sequence
information. Given the indications that certain genetically-based causes of infertility are associated with
comorbidities, and the high incidence of infertility in the population, it would be of substantial clinical impact to
make progress towards reliably identifying molecular causes of infertility. The roots of non-genetic causes are
even more difficult to ascertain, but epigenetic alterations may underlie certain types of infertility, particularly in
males where such alterations may occur in spermatogonial stem cells (SSCs). Project II has 3 Specific Aims
that seek to address these important issues in the field. Aim 1 is to functionally validate candidate genetic
variants identified from infertility patient cohorts and families in Project 1. This will be done by modeling the
variants in CRISPR-modified mice, then phenotyping the mice for not only reproductive phenotypes, but also
comorbidities that may exist in the corresponding patients, such as obesity, cancer susceptibility, or
cardiovascular disease. Aim 2 is to characterize mutations that cause infertility or subfertility phenotypes in
mice, and which may have comorbidities that have yet to be recognized. An emphasis will be on genes that are
expressed in somatic tissues in addition to the testis. Aim 3 employs a novel approach to identify epigenetic
alterations that impact SSCs, potentially leading to Sertoli Cell Only syndrome (SCOS) and non-reproductive
phenotypes. This approach involves CRISPR inhibition and activation technologies to conduct a screen of
known epigenetic modification genes that impact the efficiency somatic cell reprogramming and SSC
maintenance. In sum, this project uses diverse, cutting-edge strategies to improve the accuracy and discovery
of genetic and epigenetic causes of human male infertility and related comorbidities.

## Key facts

- **NIH application ID:** 10137292
- **Project number:** 5P50HD096723-03
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** John C Schimenti
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,146
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137292

## Citation

> US National Institutes of Health, RePORTER application 10137292, Epigenetics and Genetics of Infertility and Associated Comorbidities (5P50HD096723-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137292. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*