# Exploring the genetic architecture of structural birth defects

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $168,000

## Abstract

ABSTRACT
Structural birth defects (SBDs) impact millions of children in the US and around the world every
year. The Gabriella Miller Kids First (GMKF) program and other initiatives have committed
significant resources toward understanding the genetic basis of these conditions, yet the
genetic etiology and underlying pathogenic mechanisms remain unknown for most children that
present with SBDs. This application will focus on two classes of genomic variation that likely
contribute to this unexplained etiology in SBDs: structural variation (SV) and noncoding
regulatory variation. Broadly defined as variants >50bp in size, SVs have been discovered to be
far more prevalent and diverse in each human genome than previously appreciated. In this
proposal, we will use our recently developed SV detection algorithms from whole-genome
sequencing across GMKF SBD cohorts, and compare these findings to large population-scale
datasets in the genome aggregation database (gnomAD-SV). In addition to variant detection
and characterization, we will pursue disease association analyses in SBD cohorts. Given that
most new (de novo) mutations that occur in children reside outside of the coding sequence of
genes, it is imperative that models of disease association account for both coding and
noncoding variation. Here, we will leverage recently developed analytic frameworks of
‘category-wide association study’ (CWAS) and de novo risk score approaches to perform
association tests across all coding and noncoding single nucleotide variants, indels and
structural variants in GMKF. Finally, we will integrate genome and exome findings from cases
with neurodevelopmental disorders (NDD) to investigate commonalities in genes and pathways
associated with SBDs and NDDs. Taken together, we expect these analyses to develop a
comprehensive resource to interrogate the genetic landscape of SV and noncoding associations
across SBDs in GMKF families and population controls.

## Key facts

- **NIH application ID:** 10004116
- **Project number:** 5R03HD099547-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MICHAEL E TALKOWSKI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004116

## Citation

> US National Institutes of Health, RePORTER application 10004116, Exploring the genetic architecture of structural birth defects (5R03HD099547-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10004116. Licensed CC0.

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