# Leveraging novel methods to improve nonsyndromic cleft lip/palate gene discovery

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $186,286

## Abstract

PROJECT SUMMARY
In this proposal, we will apply robust analytical approaches to whole genome sequencing (WGS) data [obtained
from our X01 Gabriella Miller Kids First (GMKF)-funded dataset] from 20 large multigenerational families of
Hispanic and nonHispanic white ethnicities to identify variants individually and in aggregate contributing to
nonsyndromic cleft lip/palate (NSCLP). NSCLP is a common birth defect annually affecting approximately
135,000 newborns/year worldwide. Despite improvement in treatments, NSCLP imposes significant medical,
psychosocial and financial burdens to affected individuals and their families. NSCLP is complex, caused by
genetic and environmental factors, and their interactions. It is estimated that ~25% of the genetic liability for
NSCLP has been uncovered; however, most of the identified variants reflect common, modest risk-variants often
located in noncoding regions of the genome. More recently, it has been suggested that part of the missing
heritability for NSCLP lies in rare, high-risk variants, independently or via interactions with common variants.
These observations highlight the complexity of NSCLP and difficulty in unraveling risk alleles, and may explain
the lack of consistent findings among studies. In this proposal, we will select 20 large and informative families
sequenced (WGS) through the X01 mechanism and conduct genome-wide linkage and association, and PRS-
informed analyses to assess the contribution of rare and common genetic variation to familial NSCLP. In support
of our proposed approach, we have exciting and robust preliminary data showing the identification of a rare
variant segregating with NSCLP in a large multiplex family that was modified by common risk variants likely
impacting penetrance of the gene. Moreover, we showed that this variant was a null allele and resulted in
craniofacial notching mimicking NSCLP. These findings demonstrate the strengths of our approach and the high
potential for discovery of novel NSCLP genes/variants. The results of this study will provide novel and important
insights about the genetic architecture of NSCLP and lay the foundation for more extensive analysis of WGS
data from NSCLP families. The results will also inform putatively causal variants to be used in future functional
characterization studies in vitro and in vivo. Ultimately, this study will provide the groundwork for better risk
assessment for NSCLP individuals and their families that can be translated into more precise recurrence risk
counseling in clinical practice.

## Key facts

- **NIH application ID:** 10511679
- **Project number:** 1R03DE032160-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JACQUELINE T HECHT
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $186,286
- **Award type:** 1
- **Project period:** 2022-08-04 → 2024-08-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511679

## Citation

> US National Institutes of Health, RePORTER application 10511679, Leveraging novel methods to improve nonsyndromic cleft lip/palate gene discovery (1R03DE032160-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10511679. Licensed CC0.

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