Systematic identification and characterization of disease genes for the VATER/VACTERL association

VATER/VACTERL 协会疾病基因的系统鉴定和表征

• 批准号: 274036608
• 负责人: Professorin Dr. Julia Höfele
• 金额: --
• 依托单位: Kinder- und Jugendklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/274036608?language=en
• 关键词: Systematic; identification; characterization; disease; genes

The acronym VATER/VACTERL association refers to the rare, non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Aim of the present research proposal is the identification and characterization of new disease genes for the VATER/VACTERL association. The available patient cohort for human genetic studies comprises samples from 234 unrelated patients with VATER/VACTERL association, 73 patients with VATER/VACTERL-like phenotypes, additional 730 patients with (A), and 418 patients with (TE). Using exome analysis, we previously identified COL2A1, DNAH6, EEF1D, FOXF1, H3F3B, HSPA6, INPP5A, KIAA0556, MEF2C, MTA3, MYH4, PIP5K1C, PLA2G6, SHROOM4, SLC23A1, TRAP1, TRPS1, ZER1, and ZIC3 as VATER/VACTERL candidate genes. We therefore request exome analysis in additional 100 VATER/VACTERL case-parent-trios to identify additional dominant and recessive candidate genes. Large scale re-sequencing analysis of TRAP1 and ZIC3 confirmed both genes as VATER/VACTERL disease genes. Analogous, we intend to re-sequence the remaining 17 candidate genes to confirm some of them as VATER/VACTERL disease genes. For this purpose we will design a “Molecular Inversion Probe (MIP) Assay”. With this cost-effective technique we will re-sequence all 17 candidate genes in a single experiment in the remaining 1.300 patients with VATER/VACTERL association, VATER/VACTERL-like association, ARM, or TE for all of the above mentioned candidate genes. The 100 patients with VATER/VACTERL association that will undergo exome analysis will not be considered for the above mentioned re-sequencing project.The identification of new disease genes for the VATER/VACTERL association may provide new insights into mammalian pattern formation and will lead to a better understanding of molecular mechanisms responsible for the grossly disturbed development of the human vertebral, digestive, cardiac, renal and limb systems. The identification of high-penetrance causative genes will also lead to new diagnostic possibilities.

缩写VATER/VACTERL关联是指以下组成特征（CFs）的罕见、非随机共存：椎体缺损(V)、肛肠畸形（ARM） (A)、心脏缺损(C)、伴或不伴食管闭锁（TE）的气管食管瘘、肾脏畸形(R)和肢体缺损(L)。本研究计划的目的是鉴定和表征VATER/VACTERL关联的新疾病基因。可用于人类遗传学研究的患者队列包括234例与VATER/VACTERL无关的关联患者，73例VATER/VACTERL样表型患者，另外730例(A)患者和418例（TE）患者。通过外显子组分析，我们先前鉴定出COL2A1、DNAH6、EEF1D、FOXF1、H3F3B、HSPA6、INPP5A、KIAA0556、MEF2C、MTA3、MYH4、PIP5K1C、PLA2G6、SHROOM4、SLC23A1、TRAP1、TRPS1、ZER1和ZIC3是VATER/VACTERL候选基因。因此，我们要求对另外100个VATER/VACTERL病例-亲本三联组进行外显子组分析，以确定额外的显性和隐性候选基因。TRAP1和ZIC3的大规模重测序分析证实这两个基因都是VATER/VACTERL疾病基因。同样，我们打算对剩余的17个候选基因进行重测序，以确认其中一些是VATER/VACTERL疾病基因。为此，我们将设计一个“分子倒置探针（MIP）测定”。使用这种经济有效的技术，我们将在剩下的1300例VATER/VACTERL关联、VATER/VACTERL样关联、ARM或TE患者中对所有上述候选基因进行单次实验中所有17个候选基因的重测序。将进行外显子组分析的100例VATER/VACTERL关联患者将不被考虑用于上述重测序项目。VATER/VACTERL关联的新疾病基因的鉴定可能为哺乳动物模式形成提供新的见解，并将更好地理解导致人类椎体、消化、心脏、肾脏和肢体系统严重紊乱的分子机制。高外显率致病基因的鉴定也将带来新的诊断可能性。