Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate.
Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate.
复制标题
多基因风险影响非综合征性唇裂和腭裂的 PDGFRA 突变外显率。
DOI：
10.1093/hmg/ddac037
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发表时间：
2022
影响因子：
3.5
通讯作者：
Hecht,JacquelineT
中科院分区：
文献类型：
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作者：
Yu,Yao;Alvarado,Rolando;Petty,LaurenE;Bohlender,RyanJ;Shaw,DouglasM;Below,JenniferE;Bejar,Nada;Ruiz,OscarE;Tandon,Bhavna;Eisenhoffer,GeorgeT;Kiss,DanielL;Huff,ChadD;Letra,Ariadne;Hecht,JacquelineT
伴有或不伴有腭裂的非综合征性唇裂 (NSCL/P) 是一种常见的严重颅面畸形，会造成重大的医疗、社会心理和经济负担。 NSCL/P 是一种多因素疾病，遗传和环境因素发挥着病因作用。目前，通过连锁、候选基因和全基因组关联研究，仅鉴定了 25% 的 NSCL/P 遗传变异。在本研究中，采用全基因组测序和全基因组基因分型，然后进行多基因风险评分 (PRS) 和连锁分析，以确定一个三代大家庭中 NSCL/P 的遗传病因。我们在使用 pVAAST 的基于基因的关联测试中发现了 PDGFRA（c.C2740T；p.R914W）中罕见的错义变异作为潜在病因（P= 1.78 × 10−4），并且显示出外显率降低。 PRS 分析表明，常见的 NSCL/P 风险变异可能会改变变异外显率，未受影响的携带者中得分较低。连锁分析为 PRS 修改的外显率提供了额外的支持，在 PRS 调节后，可能性增加了 7.4 倍。功能表征实验表明，假定的因果变异对于体外信号活动无效；此外，pdgfrain 斑马鱼胚胎的扰动导致单侧口面裂。我们的研究结果表明，一种罕见的 PDGFRA 变异，经其他常见 NSCL/P 风险变异修饰后，对 NSCL/P 风险具有深远影响。这些数据为长期以来被认为是 NSCL/P 基础的多因素遗传提供了令人信服的证据，并可能解释一些不寻常的家族模式。
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 inPDGFRA(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 activityin vitro; further, perturbation ofpdgfrain zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rarePDGFRAvariant, 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.