Genetic Modifiers for 22q 11.2 Deletion Syndrome

描述（由申请人提供）：22q11.2缺失综合征（22 q11 DS，又称腭-心-面综合征/DiGeorge综合征）是一种先天性异常疾病，其特征为学习障碍、颅面畸形、免疫缺陷、低钙血症和心脏流出道缺陷。它发生在1/2- 4，000活产婴儿中。大多数受影响的个体具有相同的3 Mb缺失，这表明缺失区间中的基因的单倍不足是其病因学的原因。最强的候选基因之一是TBX 1，它是一种含有转录因子的T盒，在胚胎发育期间在咽器中表达。这种紊乱是完全外显的，但表现力是可变的。这一领域的最大挑战之一是确定其不同表现力的基础。随机、环境和遗传因素可能会改变表型。遗传因素或修饰剂的证据来自动物模型中的遗传研究，表现为表型、基因相互作用和Tbx 1无效突变的遗传背景效应。本研究项目的主要目标是通过在具有典型缺失的人类受试者中进行基因型-表型相关性来鉴定22 q11 DS的遗传修饰物。研究罕见疾病的部分困难在于获得足够数量的明确定义的研究对象。我们建议通过创建22q11.2联盟来解决这个问题，从而整合资源。已经确定了500例3 Mb缺失病例，作为该计划的一部分，将收集另一组500例3 Mb缺失病例。我们将使用Illumina 300，000 HapMap SNP阵列对来自300例患者的DNA进行全基因组关联研究，这些患者平均分为有显著心脏缺陷和没有心脏缺陷的患者。将对700例病例进行生物学复制并进行联合统计分析。我们将针对其他临床畸形对患者集进行重新分层。将平行进行候选基因方法，以使用Illumina定制的1，536-plex SNP阵列评估1，000个具有3 Mb缺失的22 q11 DS个体中TBX 1遗传途径中的基因。这是可能的修饰剂的显着畸形的综合征可能赋予易感性散发出生缺陷的病因不明。

DESCRIPTION (provided by applicant): The 22q11.2 deletion syndrome (22q11DS, aka velo-cardio-facial syndrome/DiGeorge syndrome) is a congenital anomaly disorder characterized by learning disabilities, craniofacial malformations, immune deficiencies, hypocalcemia and cardiac outflow tract defects. It occurs in 1/2-4,000 live births. Most affected individuals have the same 3 Mb deletion, suggesting that haploinsufficiency of gene(s) in the deleted interval is responsible for its etiology. One of the strongest candidate genes is TBX1, a T-box containing transcription factor, expressed in the pharyngeal apparatus during embryonic development. The disorder is fully penetrant but the expressivity is variable. One of the greatest challenges in this field is to determine the basis for its varied expressivity. Stochastic, environmental and genetic factors likely modify the phenotype. Evidence for genetic factors or modifiers, derives from genetic studies in animal models in the form of phenocopies, gene interactions and genetic background effects of Tbx1 null mutations. The major goal of this research program is to identify genetic modifiers for 22q11DS by performing genotype-phenotype correlations in human subjects with the typical deletion. Part of the difficulty in studying a rare disorder, is to obtain sufficient numbers of well-defined study subjects. We propose to solve this problem by creating a 22q11.2 consortium, thereby combining resources. Five hundred cases with the 3 Mb deletion have already been ascertained and another set of 500 with the 3 Mb deletion will be collected as part of this program. We will perform a whole genome association study on the DNA from 300 cases divided equally among those with significant heart defects and without, using Illumina 300,000 HapMap SNP arrays. A biological replication on 700 cases and a joint statistical analysis will be performed. We will re-stratify the patient set for other clinical malformations. A candidate gene approach will be undertaken in parallel, to assess genes in the genetic pathway of TBX1 in 1,000, 22q11DS individuals with the 3 Mb deletion, using the Illumina custom 1,536-plex SNP arrays. It is likely that modifiers for the salient malformations in the syndrome may confer susceptibility to sporadic birth defects with unknown etiologies.