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

首字母缩写Vater/Vacterl Association指的是以下成分特征(CF)罕见、非随机地同时出现：脊椎缺陷(V)、肛门直肠畸形(A)、心脏缺陷(C)、气管食管瘘伴或不伴食道闭锁(TE)、肾畸形(R)和肢体缺陷(L)。本研究的目的是为Vater/Vacterl协会鉴定和鉴定新的疾病基因。可用于人类遗传学研究的患者队列包括234名Vater/Vacterl相关性无关患者、73名Vater/Vacterl样表型患者、另外730名(A)患者和418名(TE)患者的样本。利用外显子组分析，我们已确定COL2A1、DNAH6、EEF1D、FOXF1、H3F3B、HSPA6、INPP5A、KIAA0556、MEF2C、MTA3、MYH4、PIP5K1C、PLA2G6、SHROOM4、SLC23A1、TRAP1、TRPS1、ZER1和ZIC3为Vater/Vacterl候选基因。因此，我们要求对另外100个Vater/Vacterl病例-亲本三元组进行外显组分析，以确定额外的显性和隐性候选基因。对TRAP1和ZIC3进行大规模重新测序分析，证实这两个基因为Vater/Vacterl病基因。类似地，我们打算对剩下的17个候选基因重新测序，以确认其中一些是Vater/Vacterl病基因。为此，我们将设计一种“分子反转探针(MIP)分析”。有了这项经济高效的技术，我们将在一次实验中对其余1.300名患有瓦特尔/瓦克特尔关联、瓦特/瓦克特尔样关联、ARM或TE的患者的所有17个候选基因进行重新测序，以获得上述所有候选基因。将接受外显子组分析的100名Vater/Vacterl关联患者将不会被考虑用于上述重新测序项目。为Vater/Vacterl关联识别新的疾病基因可能为哺乳动物模式的形成提供新的见解，并将有助于更好地理解导致人类脊椎、消化、心脏、肾脏和四肢系统严重发育障碍的分子机制。高外显性致病基因的识别也将带来新的诊断可能性。

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.