# Inherited and de novo genetic variants relevant to familial, recurrent and sporadic stillbirth

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $620,577

## Abstract

PROJECT SUMMARY/ABSTRACT
 Stillbirth, fetal death occurring at least 20 weeks’ gestation, is one of the most common adverse pregnancy
outcomes, affecting over 3 million pregnancies per year worldwide. Stillbirth leads to substantial economic and
emotional burden on affected families and the health care system. Women experiencing stillbirth are at
increased risk of its recurrence and other obstetric complications in subsequent pregnancies. Though an
etiology may be found in some couples, stillbirth is unexplained in about 50% of cases. Sadly, emotional
ordeals for families are exacerbated by widespread misconceptions about unexplained stillbirths, such as it
being a rare occurrence, and by increased feelings of self-blame and guilt. Apart from infrequent aneuploidies,
underlying causal genetic factors of unexplained cases are largely unknown.
 Recently, we showed that stillbirth aggregates in families, suggesting that investigating genes in high-risk
familial stillbirth pedigrees will reveal important insights into pathogenic heritable genes. Additionally, by whole-
exome sequencing (WES) of maternal-offspring dyads, we identified small genetic abnormalities that were
previously impossible to ascertain.However, the results from our WES analysis pose many challenges for
interpretation and identification of pathogenic variants affecting regulatory elements or a large and diverse set
of genes. Whole genome sequencing (WGS) analysis of DNA from both parents, stillbirths, and live births,
offers the opportunity to comprehensively detect a complete set of genetic abnormalities (e.g., single-
nucleotide polymorphisms, insertion/deletions, and structural variants, including the rest of the genome that
are biochemically active). In a pilot WGS study using DNA from parents, unexplained recurrent fetal death
including stillbirths, and live births, we showed that inherited and newly occurring, i.e., de novo variants may
be relevant to fetal death. With a larger WGS study and novel shared risk variants analyses in pedigrees, we
can identify inherited and de novo variants as causal and contributory factors for stillbirth. The findings will lead
to improved risk stratification and discovery of novel pathophysiologic pathways and therapeutic targets.
Therefore, we propose the following Specific Aims: Aim 1) Identify novel inherited variants relevant to familial
and recurrent stillbirth, Aim 2) Identify de novo variants that are part of the ‘intolerome’ and relevant to
sporadic stillbirth. We will conduct WGS analysis using DNA from both parents and their offspring (stillbirths
and live births). The scientific aims of this study are complemented and enhanced by the proposed team’s
overall commitment and expertise in the field of reproductive medicine and in stillbirth genetic research as well
as existing IRB-approved data and samples. Our study will have a significant impact by providing an
explanation for stillbirth, facilitating bereavement and emotional closure...

## Key facts

- **NIH application ID:** 10914284
- **Project number:** 5R01HD112836-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Tsegaselassie Workalemahu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,577
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914284

## Citation

> US National Institutes of Health, RePORTER application 10914284, Inherited and de novo genetic variants relevant to familial, recurrent and sporadic stillbirth (5R01HD112836-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914284. Licensed CC0.

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