PDF(Pubmed)
Abstract：
The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.
摘要：
缩写VATER/VACTERL是指以下成分特征（CFs）的罕见非随机关联：椎骨缺损（V），肛门直肠畸形（ARM）（A），心脏异常（C），伴或不伴食管闭锁（TE）的气管食管瘘，肾畸形(R),和肢体异常（L）。为了临床诊断，需要至少三个CFs的存在，仅出现两个CFs的个人被归类为VATER/VACTERL类。大多数VATER/VACTERL个体显示肾表型。到目前为止，FGF8，FOXF1，HOXD13，LPP，TRAP1,PTEN,和ZIC3已与VATER/VACTERL协会相关联；然而，大规模重新测序只能确认TRAP1和ZIC3为VATER/VACTERL疾病基因，两者都与肾脏表型有关。在这项研究中,我们对21例具有肾VATER/VACTERL或VATER/VACTERL样表型的个体及其家庭进行了外显子组测序,以确定潜在的新的遗传原因.外显子组分析分别在B9D1，FREM1，ZNF157，SP8，ACOT9和TTLL11中的六个个体（29％）中确定了双等位基因和X染色体半合子的潜在致病性变异。在线工具GeneMatcher揭示了另一个在ZNF157中具有变体的个体。我们的研究表明，六个双等位基因和X染色体半合子VATER/VACTERL疾病基因均涉及人类肾脏畸形的表达。
