Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate
| Autor: | 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 |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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