目的 对4例不同严重程度的先天性骨病患儿进行基因诊断以明确其遗传学病因。总结临床特点并进行基因型-表型分析。方法 收集4例患儿的临床资料，采集患儿及父母外周血并提取DNA，患儿行全外显子组测序，根据ACMG遗传变异分类标准与指南判断变异位点致病性，对患儿及父母进行Sanger测序验证。结果 4例患儿均携带TRPV4基因杂合变异，其中2个错义变异遗传自患病父母，1个缺失插入变异和1个错义变异为新生变异，分别为c.2077G>A (p.Val693Met)，c.1199G>A (p.Arg400Gln)，c.1657delinsACTA (p.Tyr553delinsThrAsn)，和c.259G>A (p.Glu87Lys)，以上位点国内外未见报道。1-3号患儿有不同程度的身材矮小，4例患儿均有先天性脊柱侧弯及其他骨骼系统异常。分别诊断为轻型变形性骨发育不良、3型常染色体显性短躯干、变形性骨发育不良合并类扭伤型侏儒及经典型变形性骨发育不良。携带相同变异的患儿父亲/母亲有轻度的骨骼畸形。结论 TRPV4基因不同位点变异引起的先天性骨病表型互有重叠但严重程度差异较大，可根据分子诊断结果进行鉴别诊断及临床干预。

Objective To identify the genetic causes of four patients with different severity of congenital skeletal disorder by genetic diagnosis, and to summarize the clinical characteristics and analyze the genotype-phenotype. Methods The clinical data of four patients were collected. The peripheral blood of the patients and their parents were collected and DNA was extracted. Whole exome sequencing of patients was performed and variants were classified following the interpretation standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. Putative pathogenic variants were verified by Sanger sequencing. Results The four patients all carried TRPV4 heterozygous variants. Two missense variants were inherited from affected parents, and one deletion insertion variant and missense variant were de novo: c.2077G>A (p.Val693Met), c.1199G>A (p.Arg400Gln), c.1657delinsACTA (p.Tyr553delinsThrAsn) and c.259G>A (p.Glu87Lys). None of these variants have been previously reported. Patients 1-3 had varying degrees of short stature, and all 4 had congenital scoliosis and other skeletal deformities. They were diagnosed as mild Metatropic Dysplasia, Autosomal Dominant Brachyomia type 3, Parastremmatic Dysplasia with Metatropic Dysplasia, and classic Metatropic Dysplasia respectively. Their parents with the same variant also had mild bone deformity. Conclusions The phenotypes of congenital skeletal disorders caused by different variants in TRPV4 gene were widely heterogeneous. Patients often present with overlapping skeletal system abnormalities. Therefore, differential diagnosis and clinical intervention can be conducted according to the molecular diagnosis results.