# Forward genetic analysis of congenital craniofacial malformations

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2022 · $527,793

## Abstract

Craniofacial anomalies are among the most common congenital birth defects (>1 in 700
live births) with a large, but poorly understood, genetic component. The overall objective
of this application is to take a human genetic approach to identify the genetic causes of
congenital craniofacial malformations with complementary animal model studies. Our
central hypothesis is that careful selection (based on pedigree analysis, phenotypic
presentation, etc.) and genomic sequencing of pedigrees will allow us to identify novel
causes of craniofacial malformations and facilitate experiments to uncover the underlying
mechanisms. The rationale of this proposed research is that identification of variants
causing craniofacial malformations will improve our understanding of the underlying
pathogenic mechanisms, inform patient counseling, and ultimately lead to improved
diagnosis, treatment, and patient care. We plan to test this central hypothesis and
accomplish the goals of this application by pursuing the following specific aims: 1) use
whole genome sequencing to identify variants leading to human syndromic cleft lip and
palate, 2) determine the mechanism of Fzd2 truncation pathogenesis in skeletal
development, and 3) perform functional analysis of candidate variants in novel human
craniofacial malformations. Aim 1 will be accomplished by whole genome sequencing of
selected patients from our CCHMC cohort. In Aim 2, we will further study a novel mouse
model of FZD2 omodysplasia to evaluate the role on non-canonical Wnt signaling in this
disorder. In Aim 3, we will apply our expertise in creation and study of mouse models to
understand the molecular mechanism of variants identified in affected human probands.
The results from this proposal will further identify genes essential for human craniofacial
development and have direct and persistent relevance for craniofacial developmental
biology, human genetics and genetic counseling. By identifying novel roles for single
genes, entire gene regulatory networks can often be implicated which can dramatically
increase the range of potential therapeutic targets. Moreover, the novel animal models
generated as part of these studies can be further utilized as tools for understanding basic
mechanism(s) of disease and potentially as platforms for testing therapeutic
interventions in future studies. For clinicians, increased understanding of the specific
genes involved in craniofacial development and connectivity leads to more effective
diagnosis, treatment, risk-assessment, and family planning.

## Key facts

- **NIH application ID:** 10461220
- **Project number:** 5R01DE027091-04
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Rolf W Stottmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $527,793
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461220

## Citation

> US National Institutes of Health, RePORTER application 10461220, Forward genetic analysis of congenital craniofacial malformations (5R01DE027091-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461220. Licensed CC0.

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