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

非综合征性口面裂是世界上最常见的出生缺陷之一。遗传变异被认为在非综合征性唇腭裂的风险中起主要作用;事实上，迄今为止已经确定了几个遗传风险位点。然而，这些基因座累积起来只能解释部分遗传力，并且对于大多数这些基因座，尚未确定具体的致病变异。此外，最近的工作表明，亚临床裂缝相关的表型可能包括部分的裂缝表型谱，并可能作为潜在的裂缝的责任指标。这种裂缝相关表型的遗传学还没有很好地理解。该提案将寻求填补关于导致明显形式的裂缝和相关亚临床表型的遗传变异的知识的差距。在本CIDR访问建议中，我们要求对我们先前收集的队列进行基因分型服务，包括口面裂病例、其直系亲属和无唇裂病史的对照组。我们将使用这些数据进行口面裂、裂亚型（例如，单独唇裂、唇腭裂、单独腭裂）和相关亚临床表型。了解口面裂的遗传结构和相关的亚临床特征可能最终导致改善风险和复发的预测，并可能为新的预防或治疗干预提供信息。

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.