Abstract：
Spondyloepi(meta)physeal dysplasias (SE[M]D) are a group of inherited skeletal disorders that mainly affect bone and cartilage, and next-generation sequencing has aided the detection of genetic defects of such diseases. In this study, we aimed to identify causative variants in four Chinese families associated with SE(M)D.
We recruited four unrelated Chinese families all displaying short stature and growth retardation. Clinical manifestations and X-ray imaging were recorded for all patients. Candidate variants were identified by whole-exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity was assessed by conservation analysis, 3D protein modeling and in silico prediction, and was confirmed according to American College of Medical Genetics and Genomics.
Three novel SE(M)D-related variants c.1090dupG, c.7168 T > G, and c.2947G > C in ACAN, and one reported variant c.712C > T in PAPSS2 were identified. Among them, c.1090dupG in ACAN and c.712C > T in PAPSS2 caused truncated protein and the other two variants led to amino acid alterations. Conservation analysis revealed sites of the two missense variants were highly conserved, and bioinformatic findings confirmed their pathogenicity. 3D modeling of mutant protein encoded by c.7168 T > G(p.Trp2390Gly) in ACAN proved the structural alteration in protein level.
Our data suggested ACAN is a common pathogenic gene of SE(M)D. This study enriched the genetic background of skeletal dysplasias, and expanded the mutation spectra of ACAN and PAPSS2.
We recruited four unrelated Chinese families all displaying short stature and growth retardation. Clinical manifestations and X-ray imaging were recorded for all patients. Candidate variants were identified by whole-exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity was assessed by conservation analysis, 3D protein modeling and in silico prediction, and was confirmed according to American College of Medical Genetics and Genomics.
Three novel SE(M)D-related variants c.1090dupG, c.7168 T > G, and c.2947G > C in ACAN, and one reported variant c.712C > T in PAPSS2 were identified. Among them, c.1090dupG in ACAN and c.712C > T in PAPSS2 caused truncated protein and the other two variants led to amino acid alterations. Conservation analysis revealed sites of the two missense variants were highly conserved, and bioinformatic findings confirmed their pathogenicity. 3D modeling of mutant protein encoded by c.7168 T > G(p.Trp2390Gly) in ACAN proved the structural alteration in protein level.
Our data suggested ACAN is a common pathogenic gene of SE(M)D. This study enriched the genetic background of skeletal dysplasias, and expanded the mutation spectra of ACAN and PAPSS2.
摘要：
Spondyloepi（meta）physeal发育不良（SE[M]D）是一组遗传性骨骼疾病，主要影响骨骼和软骨，下一代测序有助于检测此类疾病的遗传缺陷。在这项研究中,我们旨在确定与SE（M）D相关的四个中国家庭的致病变异。
我们招募了四个不相关的中国家庭，他们都表现出身材矮小和发育迟缓。记录所有患者的临床表现和X线影像。通过全外显子组测序(WES)鉴定候选变体并通过Sanger测序验证。致病性通过保守性分析进行评估，三维蛋白质建模和计算机预测，并根据美国医学遗传学和基因组学学院证实。
三个新的SE（M）D相关变体c.1090dupG，c.7168T>G，和c.2947G>C在ACAN，并在PAPSS2中鉴定出一个报道的变异体c.712C>T。其中,ACAN中的c.1090dupG和PAPSS2中的c.712C>T引起截短的蛋白质，其他两个变体导致氨基酸改变。保守分析显示两个错义变异的位点高度保守，和生物信息学发现证实了它们的致病性。c.7168T>G编码的突变蛋白的3D建模（p。Trp2390Gly）在ACAN中证明了蛋白质水平的结构改变。
我们的数据表明ACAN是SE(M)D的常见致病基因。本研究丰富了骨骼发育不良的遗传背景,并扩展了ACAN和PAPSS2的突变谱。
我们招募了四个不相关的中国家庭，他们都表现出身材矮小和发育迟缓。记录所有患者的临床表现和X线影像。通过全外显子组测序(WES)鉴定候选变体并通过Sanger测序验证。致病性通过保守性分析进行评估，三维蛋白质建模和计算机预测，并根据美国医学遗传学和基因组学学院证实。
三个新的SE（M）D相关变体c.1090dupG，c.7168T>G，和c.2947G>C在ACAN，并在PAPSS2中鉴定出一个报道的变异体c.712C>T。其中,ACAN中的c.1090dupG和PAPSS2中的c.712C>T引起截短的蛋白质，其他两个变体导致氨基酸改变。保守分析显示两个错义变异的位点高度保守，和生物信息学发现证实了它们的致病性。c.7168T>G编码的突变蛋白的3D建模（p。Trp2390Gly）在ACAN中证明了蛋白质水平的结构改变。
我们的数据表明ACAN是SE(M)D的常见致病基因。本研究丰富了骨骼发育不良的遗传背景,并扩展了ACAN和PAPSS2的突变谱。
