# Identifying novel genetic risks for cleft palate using whole genome sequencing

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $41,708

## Abstract

SUMMARY
Orofacial clefts (OFCs) are the most common craniofacial congenital anomalies and can be categorized into two
large groups: cleft of the upper lip with or without a cleft palate (CL/P) and cleft palate only (CP). These birth
defects are easily recognizable, and although the long-term prognosis is favorable with intervention, affected
individuals typically undergo multiple surgical procedures, may have abnormal dentition, recurrent ear infections,
speech and hearing problems, and have higher rates of morbidity and mortality later in life. Despite sharing a
defect of the palate, CP and CL/P are considered etiologically distinct. It is evident that both CP and CL/P are
highly heritable, and while dozens of well-established genetic risk loci have been identified for CL/P, only a few
loci have been identified for CP. Historically, these studies have evaluated CP cases as a whole, rather than by
stratifying by the subtypes of CP that are defined by the part of the palate that is affected. Thus, the relative lack
of common variants may be due to genetic heterogeneity among phenotypic subtypes which dilutes the ability
to detect associated variants when evaluated together. Alternatively, and/or concurrently, CP etiology may be
more closely aligned with that of other structural birth defects, such as congenital heart disease, which often
result from de novo mutations (DNMs) and inherited rare variants of large effect sizes. To elucidate the genetic
architecture of CP in the context of these possibilities, I will utilize whole genome sequencing (WGS) data from
a cohort of 518 CP cases consisting primarily of case-parent trios, and encompassing diverse populations and
all subtypes of CP by 1) evaluation of the genetic heterogeneity of CP subtypes for common and rare variants
utilizing biologically relevant genes from transcriptomic data of the embryonic mouse palate and 2) identification
of rare variants segregating with disease in multiplex families, followed by investigation of segregating variants
in the full cohort. The trio-based nature of this cohort is particularly useful for discovery as it allows for common
and rare variant analysis by transmission disequilibrium tests, which are robust to population stratification, as
well as identification of high confidence DNMs. To further maximize discovery power, these analyses will be
focused on coding variants that meet specific criteria for pathogenicity prediction to best prioritize potentially
causal variants. Upon completion of this research, our understanding of the genetic risks for CP and each of the
subtypes will be significantly advanced. Knowledge of novel risk factors will not only improve prediction,
prevention, and prognosis of CP, but also elucidate mechanisms of normal and abnormal palatal development.

## Key facts

- **NIH application ID:** 10692611
- **Project number:** 5F31DE032588-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Kelsey Rebecca Robinson Wallace
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $41,708
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692611

## Citation

> US National Institutes of Health, RePORTER application 10692611, Identifying novel genetic risks for cleft palate using whole genome sequencing (5F31DE032588-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692611. Licensed CC0.

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