# Harvard Reproductive Endocrine Sciences Center

> **NIH NIH P50** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,732,450

## Abstract

Overall Summary Abstract
Our Center brings together three multidisciplinary Project teams focusing on the biologically critical question:
What is the full genetic architecture that determines the hypothalamic control of human reproduction? Using
the mendelian human disease model of Isolated GnRH Deficiency (IGD), Project 1 will accelerate its
successful novel gene discovery efforts in our existing and fully phenotyped IGD cohort of >2,000 to identify
new genes critical for human reproduction as attested to by their creation of IGD when mutated. Using whole
exome, whole genome, and RNA sequencing in selected subsets of this cohort such as those: i) sharing a 2nd
rare phenotype; ii) with known structural abnormalities; or iii) from multiplex families, we will identify a wide
range of coding and non-coding defects in this population. These resulting new ‘candidate IGD genes’ are then
forwarded to Project 3 for in vivo functional confirmation in zebrafish. Project 2 will focus its complex trait
genetic expertise on identifying new genetic loci/genes associated with the 3 commonest reproductive
disorders in women: PCOS, premature ovarian insufficiency, and hypothalamic amenorrhea. Using genome
wide association studies combined with tracking of these conditions with associated genetic loci in several
population cohorts where genotypes and phenotypes are already available (cf. Letters of Collaboration), P2 will
surface large numbers of new, common, and milder loss of function (LoF) mutations in genes underlying these
diseases. As sufficient new loci/genes become apparent, P2 will assemble these new genes into new biology
pathways regulating various physiologic and pathologic controls of human reproduction. P3 will validate each
of these new candidate genes using a zebrafish bioassay. By then recalling our IGD and population patients
harboring these novel mutations to re-phenotype them and thus define the full, unbiased phenotypic spectrum
of associated phenotypes, penetrance, varied expressivity, and interactions with other genes associated with
each new genes in our Educational/Outreach Core. Collectively, these inter-disciplinary, integrated
approaches, techniques, and expertise will provide a deeper understanding of the range of reproductive
defects associated with these new genes that are critical for normal human reproduction.

## Key facts

- **NIH application ID:** 9910420
- **Project number:** 5P50HD028138-30
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephanie Beth Seminara
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,732,450
- **Award type:** 5
- **Project period:** 1997-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910420

## Citation

> US National Institutes of Health, RePORTER application 9910420, Harvard Reproductive Endocrine Sciences Center (5P50HD028138-30). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9910420. Licensed CC0.

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