Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Mol Genet Genomic Med. 2022 May;10(5):e1916. doi: 10.1002/mgg3.1916. Epub 2022 Mar 9.
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.
脊椎干骺端发育不良（SE[M]D）是一组主要影响骨骼和软骨的遗传性骨骼疾病，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，我们旨在鉴定与 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，这些家庭均表现出身材矮小和生长迟缓。对所有患者进行临床表型和 X 射线成像记录。通过全外显子组测序（WES）鉴定候选变异，并通过 Sanger 测序验证。通过保守性分析、3D 蛋白建模和计算机预测评估致病性，并根据美国医学遗传学与基因组学学院确认。
在 ACAN 中鉴定出三个新的 SE（M）D 相关变异 c.1090dupG、c.7168 T>G 和 c.2947G>C，以及 PAPSS2 中的一个报道变异 c.712C>T。其中，ACAN 中的 c.1090dupG 和 PAPSS2 中的 c.712C>T 导致截短蛋白，另外两个变异导致氨基酸改变。保守性分析显示两个错义变异的位点高度保守，生物信息学发现证实了它们的致病性。ACAN 中编码 c.7168 T>G（p.Trp2390Gly）的突变蛋白的 3D 建模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。
