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

Yao Yu, Rolando Alvarado, Lauren E. Petty, Ryan J. Bohlender, Douglas M. Shaw, Jennifer E. Below, Nada Bejar, Oscar E. Ruiz, Bhavna Tandon, George T. Eisenhoffer, Daniel L. Kiss, Chad D. Huff, Ariadne Letra, Jacqueline T. Hecht

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 languageEnglish (US)
Pages (from-to)2348-2357
Number of pages10
JournalHuman Molecular Genetics
Issue number14
StatePublished - Jul 15 2022


  • 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


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