Cleft Lip Genetics: A Multi Center International Consortium

描述（由申请人提供）： 这种竞争性更新的目标是确定人类唇裂伴或不伴腭裂（CL/P）的遗传基础，这是一种常见的遗传复杂的出生缺陷。我们已经完成了初始赠款的所有3个具体目标，包括：1）招募了130多个大家庭和500个受影响的儿童/父母三人组。2)候选基因的遗传分析，在哥伦比亚和俄亥俄州家庭中均显示阳性结果。这些基因座将用作基因-基因相互作用检验中的协变量。3)完成全基因组连锁扫描，确定了其他阳性基因座，包括先前未确定的9 q22 -33的主要基因座。通过成功应用于遗传疾病研究中心（CIDR：Lidral PI）与Arcos-Burgos，Marazita和Murray博士合作完成的基因组扫描，以评估来自7个不同人群的600多个CL/P家族，在其中4个人群中发现了9 q22 -33（合并LOD=6.6）的高度显著结果，哥伦比亚家族产生了最显著的结果。更新的重点是定位克隆9 qCL/P基因座，其2-LOD间隔为18 cM。最初的精细定位将通过对相同的600个家庭的1536个SNP的Illumina面板进行基因分型来完成，以通过连锁缩小区域并筛选关联。作为成功的试点项目申请（Lidral PI）的一部分，将由CIDR进行基因分型。为了获得更大的力量，我们与哥伦比亚的另一个中心建立了合作关系，这是一个独特的美洲土著印第安人，西班牙人和非洲人的混合人口。这种混合物可能导致一个强大的连锁不平衡模式，允许关联研究在一个低得多的标记密度。我们建议探讨这是否存在于我们的研究人群中，如果是这样，应用新兴的混合方法。总的来说，我们将能够招募总共超过300个扩展家庭和2000个三人家庭，这将是复制和未来研究的基础，以精细绘制其他阳性基因座并确定基因-基因相互作用。为了帮助优先考虑哪些基因应该测序，我们建议在小鼠CL/P模型中确定关键区域内未表征基因的胚胎面部表达。通过使用互补的小鼠和人类遗传学，该项目将确定正常面部发育所必需的基因和途径，从而可以制定CL/P的预防策略。

DESCRIPTION (provided by applicant): The goal of this competitive renewal is to identify the genetic basis in humans for cleft lip with or without cleft palate (CL/P), which is a common and genetically complex birth defect. We have accomplished all 3 of the specific aims of the initial grant, including: 1) Recruitment of more than 130 extended families and 500 affected child/parent trios. 2) Genetic analysis of candidate genes, which revealed positive results in both Colombian and Ohio families. These loci will be used as covariates in gene-gene interaction tests. 3) Completion of a genome wide linkage scan which identified additional positive loci, including a previously unidentified major locus at 9q22-33. A genome scan, accomplished by the successful application to the Center for Inherited Disease Research (CIDR: Lidral PI) in collaboration with Drs. Arcos-Burgos, Marazita and Murray to evaluate over 600 CL/P families from 7 different populations, revealed a highly significant result to 9q22-33 (combined LOD=6.6) in 4 of these populations with the Colombian families yielding the most significant results. The specific focus of the renewal is to positionally clone the 9q CL/P locus which has an 18cM 2-LOD interval. The initial fine-mapping will be accomplished by genotyping an Illumina panel of 1536 SNPs on the same 600 families to narrow the region by linkage and to screen for association. The genotyping will be performed by CIDR as part of a successful pilot project application (Lidral PI). For greater power we have established collaborations with another center in Colombia that is a unique admixed population of Native American Indians, Spaniards and Africans. This admixture likely results in a powerful pattern of linkage disequilibrium that permits association studies at a much lower marker density. We propose to explore whether this exists in our study population and if so apply emerging admixture methods. All total, we will be able to recruit a total of more than 300 extended and 2000 trio families that will be the basis for replication and for future studies to fine-map the other positive loci and identify gene-gene interactions. To aid in prioritizing which genes should be sequenced, we propose to determine in a mouse CL/P model the embryonic facial expression of uncharacterized genes within the critical region. Through the use of complimentary mouse and human genetics this project will identify genes and pathways essential for normal facial development, such that preventive strategies for CL/P can be developed.