# Genetic modifiers of Van der Woude syndrome

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $585,416

## Abstract

PROJECT SUMMARY
Reduced penetrance and variable expressivity are common, but poorly understood, features of most
monogenic diseases. Genetic modifiers are possible factors to contribute to this phenotypic variability and blur
the traditional distinction between monogenic and complex disease. Here, we propose to study the most
common orofacial cleft syndrome (Van der Woude syndrome, VWS) and nonsyndromic orofacial clefts (OFCs),
which intersect both in phenotype and in genetic etiology, as a model to understand reduced penetrance and
variable expressivity. VWS occurs in 1 in 35,000 individuals and accounts for 2% of all OFCs. The features of
VWS include an OFC and/or lower lip pits, but 15% of VWS patients present with an isolated OFC, making
them indistinguishable from nonsyndromic OFC patients. Mutations in the genes IRF6 or GRHL3 cause VWS,
but approximately 20% of VWS patients currently lack a molecular diagnosis. Furthermore, there are few
genotype-phenotype correlations for known mutations and patient phenotypes. By contrast, GWAS of
nonsyndromic OFCs have identified a number of risk factors, some of which we have shown increase risk for
specific types of OFCs or act as modifiers of OFC subtypes. We have assembled the largest collection of VWS
families in the world and whole genome sequence data from over 900 nonsyndromic OFC trios. We propose to
use whole genome sequencing and SNP genotyping in both cohorts to identify the remaining genetic mutations
for VWS, determine the relationship between those genes/regions with nonsyndromic OFCs, and identify rare
and common modifiers of VWS and OFC phenotypes. These analyses will provide further insight into the
genetic architecture of VWS and OFCs and will serve as a model for exploring links between other Mendelian
disorders that share phenotypes with complex traits.

## Key facts

- **NIH application ID:** 9977166
- **Project number:** 5R01DE028342-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ELIZABETH JANE LESLIE-CLARKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,416
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977166

## Citation

> US National Institutes of Health, RePORTER application 9977166, Genetic modifiers of Van der Woude syndrome (5R01DE028342-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977166. Licensed CC0.

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