Abstract
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common, severe craniofacial malformation that imposes significant medical, psychosocial and financial burdens. NSCL/P is a multifactorial disorder with genetic and environmental factors playing etiologic roles. Currently, only 25% of the genetic variation underlying NSCL/P has been identified by linkage, candidate gene and genome-wide association studies. In this study, whole-genome sequencing and genome-wide genotyping followed by polygenic risk score (PRS) and linkage analyses were used to identify the genetic etiology of NSCL/P in a large three-generation family. We identified a rare missense variant in PDGFRA (c.C2740T; p.R914W) as potentially etiologic in a gene-based association test using pVAAST (P = 1.78 × 10-4) and showed decreased penetrance. PRS analysis suggested that variant penetrance was likely modified by common NSCL/P risk variants, with lower scores found among unaffected carriers. Linkage analysis provided additional support for PRS-modified penetrance, with a 7.4-fold increase in likelihood after conditioning on PRS. Functional characterization experiments showed that the putatively causal variant was null for signaling activity in vitro; further, perturbation of pdgfra in zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rare PDGFRA variant, modified by additional common NSCL/P risk variants, have a profound effect on NSCL/P risk. These data provide compelling evidence for multifactorial inheritance long postulated to underlie NSCL/P and may explain some unusual familial patterns.
Original language | English (US) |
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Pages (from-to) | 2348-2357 |
Number of pages | 10 |
Journal | Human Molecular Genetics |
Volume | 31 |
Issue number | 14 |
DOIs | |
State | Published - Jul 15 2022 |
Keywords
- Animals
- Cleft Lip/genetics
- Cleft Palate/genetics
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genotype
- Multifactorial Inheritance
- Mutation
- Penetrance
- Polymorphism, Single Nucleotide
- Zebrafish/genetics
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
- Molecular Biology