PDF(Pubmed)
Abstract：
Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O-sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age.
摘要：
骨骼发育不良（SD）是高度异质性的疾病，由40种临床亚型组成，是456种明确描述的人类综合征的一部分。这里,我们招募了来自巴基斯坦信德省偏远地区的近亲，有14名受影响的人身材矮小，脊柱侧后凸,关节脱位,马蹄内翻足,心脏瓣膜异常和进行性双侧混合性听力损失。为了鉴定这个家族的致病变异，在一个受影响的个体和一个正常个体中进行全外显子组测序（WES），这揭示了与表型相关的CHST3中的一个新的颠换突变(c.8022G>T;p.Glu268*)。CHST3编码软骨素6-O-磺基转移酶-1（C6ST-1）酶，该酶对于软骨中发现的蛋白聚糖的硫酸化至关重要。以前,CHST3中的突变主要在散发性SD病例中报道，主要有严重的脊柱异常，关节脱位,关节挛缩,和马蹄。该家族中受影响个体的临床和放射学检查为CHST3等位基因的表型谱和疾病随年龄的进展提供了新的见解。
