PDF(Pubmed)
Abstract：
Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFCs. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.
摘要：
非综合征性口面裂痕（NSOFC）是常见的出生缺陷，病因复杂。虽然已经确定了60多个常见的风险位点，他们只解释了NSOFCs遗传力的一小部分。罕见的变异与缺失的遗传力有关。因此，我们的研究旨在鉴定富含与NSOFCs相关的非同义罕见编码变异的基因.我们的样本包括814例非综合征性唇裂伴或不伴腭（NSCL/P），205非综合征性腭裂（NSCPO），和来自尼日利亚的2150名无关的控制儿童，加纳,埃塞俄比亚。我们使用三种罕见变异塌陷模型分别对每种表型进行了基于基因的分析：（1）蛋白质改变（PA），(2)仅错义变体(MO);和(3)仅丧失功能变体(LOFO)。随后，我们利用相关转录组学数据评估相关基因表达,并使用gnomeAD数据库检查其突变约束.总的来说,13个基因显示暗示性关联(p=E-04)。其中,八个基因（ABCB1，ALKBH8，CENPF，CSAD,EXPH5，PDZD8，SLC16A9和TTC28）在面部形成过程中在相关的小鼠和人类颅面组织中一致表达，三个基因(ABCB1、TTC28和PDZD8)显示出统计学上显著的突变约束。这些发现强调了罕见变异在鉴定NSOFC候选基因中的作用。
