FAMILIAL VERTICAL TALUS EXOME SEQUENCING

描述（申请人提供）：垂直距骨，也称为摇底足，常见于患有多种先天性异常的患者，例如 18 三体、13 三体、远端关节弯曲和脊髓脊膜膨出。然而，近一半的垂直距骨病例是作为一种孤立的情况发生的，没有相关的异常。孤立性垂直距骨和综合征性垂直距骨的区别至关重要，因为预后和治疗结果差异很大。尽管引起垂直距骨综合征的原因有很多，但人们对孤立性垂直距骨的遗传基础知之甚少。我们实验室之前的研究提供了孤立垂直距骨主要基因座的证据，但致病基因尚未确定。为了验证一种罕见的遗传变异导致孤立性垂直距骨的假设，我们计划对一组患有家族性孤立性垂直距骨的患者进行研究。这些研究的对象将来自华盛顿大学肌肉骨骼 DNA 数据库，其中包含 3000 多个患者样本，其中包括 100 名垂直距骨患者。由于众所周知的染色体非整倍性与垂直距骨之间的关联，我们将首先评估 20 名垂直距骨患者的染色体拷贝数变异 (CNV)，其中包括来自三个常染色体显性垂直距骨家族的先证者。此前，我们通过这种方法检测小 CNV（<100kb），从而鉴定出马蹄内翻足的致病基因，马蹄内翻足是一种与垂直距骨有许多相似之处的出生缺陷。使用已知对孟德尔疾病疾病基因发现有效的补充方法，我们还将进行外显子组测序，以识别来自三个具有孤立的家族性垂直距骨家族的先证者的罕见编码突变。最后，将使用一组垂直距骨患者的合并重测序来确定候选基因的突变。从这些实验中获得的结果不仅将增进我们对垂直距骨的理解，而且将使我们能够为儿科肌肉骨骼疾病的未来研究建立方法和基础设施。

DESCRIPTION (provided by applicant): Vertical talus, also called rocker-bottom foot, commonly occurs in patients with multiple congenital abnormalities, such as trisomy 18, trisomy 13, distal arthrogryposis, and myelomeningocele. However, nearly half of all cases of vertical talus occur as an isolated condition with no associated abnormalities. Distinction between isolated vertical talus and syndromic vertical talus is critical because the prognosis and treatment outcomes vary significantly. Though there are many causes of syndromic vertical talus, the genetic basis of isolated vertical talus is poorly understood. Previous studies in our laboratory provided evidence of a major locus for isolated vertical talus, but the causative gene has not yet been identified. To test the hypothesis that a rare genetic variant is responsible for isolated vertical talus, we plan to a study a cohort of patients with familial isolated vertical talus. The subjects for these studies will come from the Washington University Musculoskeletal DNA Database containing more than 3000 patient samples, including 100 patients with vertical talus. Because of the well-known association between chromosomal aneuploidy and vertical talus, we will first evaluate for chromosomal copy number variants (CNVs) in 20 patients with vertical talus, including probands from three autosomal dominant vertical talus families. The detection of small CNVs (<100kb) with this approach previously resulted in our identification of causative genes for clubfoot, a birth defect with many similarities to vertical talus. Using a complementary approach known to be effective for disease gene discovery in mendelian disorders, we will also perform exome sequencing to identify rare coding mutations in probands from three families with isolated familial vertical talus. Finally, mutations in candidate genes will be determined using pooled resequencing in a cohort of patients with vertical talus. The results gained from these experiments will not only advance our understanding of vertical talus, but will allow us to establish the methodologies and infrastructure for future studies of pediatric musculoskeletal disorders.