ArticleHuman molecular genetics2022
Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
19 citing papers in PubMed, 15 citations in OpenAlex.
- Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate.European journal of human genetics : EJHG · 2026Article
- Advancing risk gene discovery across the allele frequency spectrum.HGG advances · 2026Review
- Rare variants in embryonic development and cell signalling genes in syndromic and non-syndromic orofacial clefts: evidence from a Colombian Caribbean cohort.Journal of human genetics · 2026Article
- Estimation of direct and indirect polygenic effects and gene-environment interactions using polygenic scores in case-parent trio studies.Nature genetics · 2026Article
- Rare variants in FAT3 as possible contributors to non-syndromic orofacial cleft risk.Human genomics · 2026Article
- Familial Oculoauriculovertebral Spectrum: A Genomic Investigation of Autosomal Dominant Inheritance.The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2026Article
- Article
- Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci.medRxiv : the preprint server for health sciences · 2026Article
- Rare missense variants inFrontiers in genetics · 2026Article
- The Evolution of Gene Sequencing Technologies: Unveiling Genetic Architecture of Nonsyndromic Orofacial Clefts.Genetics research · 2026Review
- Expanding the Genetic Landscape of Craniofacial Anomalies Through Transcriptome-Wide Association Studies.Research square · 2025Article
- Expanding the Genetic Landscape of Craniofacial Anomalies Through Transcriptome-Wide Association Studies.Research square · 2025Article
- Estimation of Direct and Indirect Polygenic Effects and Gene-Environment Interactions using Polygenic Scores in Case-Parent Trio Studies.medRxiv : the preprint server for health sciences · 2025Article
- Analysis of canine gene constraint identifies new variants for orofacial clefts and stature.Genome research · 2025Article
- Functional Validation of Noncoding Variants Associated With Nonsyndromic Orofacial Cleft.Human mutation · 2025Review
- Whole genome sequencing of a family with autosomal dominant features within the oculoauriculovertebral spectrum.medRxiv : the preprint server for health sciences · 2024Article
- Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes.Journal of human genetics · 2024Article
- Genetic Inheritance Models of Non-Syndromic Cleft Lip with or without Palate: From Monogenic to Polygenic.Genes · 2023Review
- What's Shape Got to Do With It? Examining the Relationship Between Facial Shape and Orofacial Clefting.Frontiers in genetics · 2022Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.