Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate

Hum Mol Genet. 2022 Jul 21;31(14):2348-2357. doi: 10.1093/hmg/ddac037.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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