{"doi":"10.1093/hmg/ddac037","title":"Polygenic risk impacts<i>PDGFRA</i>mutation penetrance in non-syndromic cleft lip and palate","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.","journal":"Human Molecular Genetics","year":2022,"id":256129,"datarank":0.6091776742765815,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.15249930861806804,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.15249930861806804,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":20,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":905452,"name":"Rolando Alvarado","orcid":null,"position":1,"is_corresponding":false},{"id":461620,"name":"Lauren E. Petty","orcid":"0000-0003-1619-6303","position":2,"is_corresponding":false},{"id":461621,"name":"Ryan J. Bohlender","orcid":"0000-0002-6347-0494","position":3,"is_corresponding":false},{"id":461619,"name":"Douglas M. Shaw","orcid":"0000-0001-8896-6659","position":4,"is_corresponding":false},{"id":16108,"name":"Jennifer E. Below","orcid":"0000-0002-6372-6402","position":5,"is_corresponding":false},{"id":904991,"name":"Nada Bejar","orcid":"0000-0002-0980-5951","position":6,"is_corresponding":false},{"id":747374,"name":"Oscar E. Ruiz","orcid":"0000-0002-5426-260X","position":7,"is_corresponding":false},{"id":904992,"name":"Bhavna Tandon","orcid":"0000-0002-8464-6903","position":8,"is_corresponding":false},{"id":400652,"name":"George T. Eisenhoffer","orcid":"0000-0003-0188-6782","position":9,"is_corresponding":false},{"id":589293,"name":"Dániel Kiss","orcid":"0000-0001-5033-7160","position":10,"is_corresponding":false},{"id":4466,"name":"Chad D. Huff","orcid":"0000-0002-1100-9364","position":11,"is_corresponding":false},{"id":904993,"name":"Ariadne Letra","orcid":"0000-0002-7197-6735","position":12,"is_corresponding":false},{"id":284226,"name":"Jacqueline T. Hecht","orcid":"0000-0002-9087-3379","position":13,"is_corresponding":false},{"id":4467,"name":"Yao Yu","orcid":"0000-0002-2727-1746","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:25:21.336200Z","pmid":"35147171","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}