■Weill-Marchesani综合征(WMS)是一种罕见的结缔组织疾病,其特征是基因座异质性和表达可变。患有WMS的患者被描述为身材矮小,Brachydactyly,接头刚度,先天性心脏缺陷,和眼睛异常。这种疾病以两种不同的方式遗传;该疾病的常染色体显性形式是由于FBN1的突变而发生的,隐性形式是由ADAMTS10,ADAMTS17或LTP2基因的突变引起的。
■这项研究中招募的家庭是一个有血缘关系的伊朗家庭,有一个智障女孩,被称为Sadra遗传学实验室,Shahrekord,伊朗。调查家庭成员的临床病史。进行先证者的全外显子组测序(WES)。Sanger测序用于评估候选变体在其他家族成员中的分离。
■全外显子组测序分析揭示了先证中位于FBN1基因第三个TGF-β结合蛋白样(TB)结构域的新杂合子突变(NM000138:c.206A>G:(p。Glu689Gly),NP_000129.3,在基因的外显子17中)。与Sanger测序的共分离分析证实了在谱系的受影响成员中的这种突变。
■我们的发现代表了由FBN1基因中的置换突变引起的特定WMS的常染色体显性形式。除了这种疾病的典型表现,在8岁的先证者中发现了轻度智力障碍(ID)。鉴于ID主要在ADAMTS10突变病例中报告,这个家庭在临床和基因上都是一个新病例。
UNASSIGNED: Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by locus heterogeneity and variable expressivity. Patients suffering from WMS are described by short stature, brachydactyly, joint stiffness, congenital heart defects, and eye abnormalities. This disorder is inherited in two different modes; the autosomal dominant form of the disease occurs due to a mutation in FBN1, and the recessive form results from mutations in ADAMTS10, ADAMTS17, or LTP2 genes.
UNASSIGNED: The family recruited in this study was a consanguineous Iranian family with an intellectually disabled girl referred to the Sadra Genetics laboratory, Shahrekord, Iran. The clinical history of family members was investigated. Whole-Exome Sequencing (WES) for the proband was performed. Sanger sequencing was used to assess the segregation of candidate variants in the other family members.
UNASSIGNED: Whole-exome sequencing analysis revealed a novel heterozygote mutation in the proband located at the third TGF-β-binding protein-like (TB) domain of the FBN1 gene (NM000138: c.2066A>G: (p. Glu689Gly), NP_000129.3, in exon 17 of the gene). Co-segregation analysis with Sanger sequencing confirmed this mutation in the affected members of the pedigree.
UNASSIGNED: Our findings represent an autosomal dominant form of specific WMS resulting from a substitution mutation in the FBN1 gene. In addition to the typical manifestations of the disorder, mild intellectual disability (ID) was identified in the 8-year-old proband. Given the fact that ID is primarily reported in ADAMTS10 mutated cases, this family was clinically and genetically a novel case.