PUBLICATION

Polygenic risk impacts PDGFRA mutation penetrance in nonsyndromic cleft lip and palate

Authors
Yu, Y., Alvarado, R., Petty, L.E., Bohlender, R.J., Shaw, D.M., Below, J.E., Bejar, N., Ruiz, O.E., Tandon, B., Eisenhoffer, G.T., Kiss, D.L., Huff, C.D., Letra, A., Hecht, J.T.
ID
ZDB-PUB-220212-8
Date
2022
Source
Human molecular genetics   31(14): 2348-2357 (Journal)
Registered Authors
Eisenhoffer, George, Ruiz, Oscar E.
Keywords
none
MeSH Terms
  • Cleft Lip*/genetics
  • Genetic Predisposition to Disease
  • Zebrafish/genetics
  • Genome-Wide Association Study
  • Genotype
  • Polymorphism, Single Nucleotide
  • Penetrance
  • Cleft Palate*/genetics
  • Mutation
  • Animals
  • Multifactorial Inheritance
(all 11)
PubMed
35147171 Full text @ Hum. Mol. Genet.
Abstract
Nonsyndromic 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 (WGS) 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 x 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.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Yu, Y., Alvarado, R., Petty, L.E., Bohlender, R.J., Shaw, D.M., Below, J.E., Bejar, N., Ruiz, O.E., Tandon, B., Eisenhoffer, G.T., Kiss, D.L., Huff, C.D., Letra, A., Hecht, J.T. (2022) Polygenic risk impacts PDGFRA mutation penetrance in nonsyndromic cleft lip and palate. Human molecular genetics. 31(14):2348-2357.