# Project I

> **NIH NIH P50** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2024 · $710,390

## Abstract

Summary: Project I
Since the beginning of our National Center for Translational Research in Reproduction & Infertility in 2019, our
knowledge of genetic causes of infertility has expanded dramatically. In a recent (2022) study of whole-exome
sequencing (WES) from 1,000 cases of unexplained male infertility, we identified a plausible monogenic cause
in 20% of cases. Similar diagnostic yields have been reported for other male infertility cohorts. Despite these
impressive research advances, there are two major shortcomings of our work. First, we are not identifying all
genetic causes in our patients. Second, even though we understand the genetics much better than 5 years ago,
we have not made any impact on clinical diagnosis. In this proposal, our goal is to improve the diagnostic yield
of clinical genome sequencing for male infertility in two ways. First, we aim to improve diagnostic yield with new
approaches to sequencing and interpretation of genomes of male infertility. We will transition from WES to whole
genome sequencing (WGS), and in the process, expand our analysis methods to new types of variants
detectable by WGS. We will expand our analysis to new disease models for which we have been historically
underpowered to capture, such as autosomal dominant and digenic, and to interrogate genes involved in testis
development which have been previously overlooked. These new approaches will be applied to our existing
database of >1,600 WES data from patients, >80% of which are still unsolved, and to new patients that we
continue to enroll. Second, we aim to improve translation of our research findings by organizing an international
clinical genetics community to generate and share gene and variant interpretations. In the modern clinical
genetics landscape, most diagnostic workflows rely heavily on published guidelines for the interpretation of
genetic variants. Notably, there are no official expert panels reviewing genes or variants for infertility. We will
reactivate our existing international team, which has performed gene and variant interpretation in 2018 and 2020,
to fill this gap. We will build open our expertise and accelerate our curation by creating a shared online working
environment that records and reconciles interpretations. This review environment will also provide reference
information on testis gene expression, fertility phenotypes of mutations across multiple model organisms, and
an allele frequency database built from over 1,000 genomes of male infertility cases and 600 genomes from
normozoospermic controls. At the end of this 5-year project, we believe we will have achieved a milestone that
we targeted over 10 years ago. We will have built a strong foundation of solid research in male infertility genetics,
summarized and packaged this knowledge for clinical use. We aspire that, in 2029, genome sequencing will
finally become a routine clinical test for the diagnosis of male infertility.

## Key facts

- **NIH application ID:** 10992991
- **Project number:** 2P50HD096723-06
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** DONALD F. CONRAD
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $710,390
- **Award type:** 2
- **Project period:** 2019-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992991

## Citation

> US National Institutes of Health, RePORTER application 10992991, Project I (2P50HD096723-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10992991. Licensed CC0.

---

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