TRPV4基因的两个不同变异导致变形性骨发育不良表型严重程度差异

Two different variants in the TRPV4 gene lead to metatropic dysplasia with various phenotypic severity

目的对2例临床表型严重程度有所差异的先天骨骼发育异常病例进行遗传学分析,并对检出变异进行生物信息学分析,探讨其致病性。方法本研究中,临床发现2例有不同表型严重程度的骨骼发育不良个体及其父母,并对其进行了包括染色体核型、染色体微阵列分析(CMA)和全外显子测序(WES)的序贯式遗传检测,以Sanger测序作为变异验证方法,对检出错义变异进行了生物信息学结构分析。结果2例先证者的核型及CMA结果均正常,WES在2例先证者中分别检出TRPV4基因的两个变异,一个错义变异c.2389G>A(p.E797K)和一个整码缺失变异c.1412_1414del(p.F471del)。家系验证证实2个变异均为新发变异。2个变异发生在该基因的不同结构域,对错义变异的结构分析结果支持了其致病性。结论TRPV4基因变异所导致的变形性骨发育不良表型严重程度与变异具体位置有很大的关系。

Objective To explore the pathogenicity of specific variant by carrying out genetic analysis on 2 cases of congenital skeletal dysplasia(SD)with different clinical phenotypic severity,and further bioinformatics analysis was carried out towards the genetic variants.Methods In this study,we recruited 2 SD individuals with different phenotypic severity and their parents,and performed sequential genetic assays including chromosome karyotyping,chromosome microarray analysis(CMA),and whole-exome sequencing(WES).Sanger sequencing was used as mutation validation method.We also performed in silico structural analysis on detected missense variants.Results The karyotype and CMA results of 2 probands were normal,two variants in TRPV4 gene were detected in 2 probands,respectively,including one missense variant c.2389G>A(p.E797K)and one non frameshift deletion variant c.1412_1414del(p.F471del).Family verification confirmed that the two variants were both de novo.Two variants occurred in different domains of the gene,and the pathogenicity is supported by structural analysis of the missense variant.Conclusion The severity of metatropic dysplasia caused by genetic variations in TRPV4 is highly associated with the specific location of the variation.