ILLUMINA GLOBAL DIVERSITY ARRAY (SHAFFER&MARAZITA) NIDCR FY 2020 CAN 8469539: Genetics of Orofacial Clefts, Sub-types, and Subclinical Phenotypes

非综合征性唇裂是世界范围内最常见的出生缺陷之一。遗传变异被认为在非综合征性唇裂的风险中起主要作用；事实上，到目前为止，已经确定了几个遗传风险基因。然而，这些基因座累积起来只解释了部分遗传力，对于大多数这些基因座，具体的因果变异还没有确定。此外，最近的工作表明，亚临床裂隙相关表型可能构成裂隙表型谱的一部分，并可作为潜在裂隙易感性的指标。这些与裂隙相关的表型的遗传学还不是很清楚。这项建议将寻求填补关于导致明显形式的唇裂和相关的亚临床表型的遗传变异的知识空白。在这份CIDR访问建议中，我们要求为我们之前收集的队列提供基因分型服务，这些队列包括口腔面部裂患者、他们的直系亲属和没有唇裂病史的对照。我们将使用这些数据来进行全基因组范围的口面部裂隙、裂亚型(例如，单独的唇裂、唇腭裂、单独的腭裂)以及相关亚临床表型的关联研究。了解口腔裂隙的遗传结构和相关的亚临床特征最终可能会改善风险和复发的预测，并可能为新的预防或治疗措施提供信息。

Non-syndromic orofacial clefts are one of the most common birth defects worldwide. Genetic variation is thought to play a major role in risk of non-syndromic clefts; indeed, several genetic risk loci have been identified, to date. However, these loci cumulatively explain only part of the heritability, and for most of these loci, the specific causal variants have not yet been determined. Moreover, recent work has suggested that subclinical cleft-related phenotypes may comprise part of the cleft phenotypic spectrum, and may serve as indicators of the underlying cleft liability. The genetics of such cleft-related phenotypes is not well understood. This proposal will seek to fill the gap in knowledge regarding the genetic variants leading to overt forms of clefts and related subclinical phenotypes. In this CIDR access proposal we request genotyping services for our previously collected cohort comprising cases with orofacial clefts, their immediate family members, and controls with no history of clefts. We will use these data to perform genome-wide association studies for orofacial clefts, cleft subtypes (e.g., cleft lip alone, cleft lip and palate, cleft palate alone), and related subclinical phenotypes. Understanding the genetic architecture of orofacial clefts and related subclinical features may ultimately lead to improved prediction of risk and recurrence, and may inform new preventive or therapeutic interventions.