Background： Congenital cataract （CC） is the leading cause of visual impairment or blindness in children worldwide. Because of highly genetic and clinical heterogeneity, a molecular diagnosis of the lens disease rem...Background： Congenital cataract （CC） is the leading cause of visual impairment or blindness in children worldwide. Because of highly genetic and clinical heterogeneity, a molecular diagnosis of the lens disease remains a challenge. Methods： In this study, we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure, pedigree validation, and molecular dynamics （MD） simulation. Results： A novel 15 bp deletion on GJA8 （c.426_440delGCTGGAGGGGACCCT or p. 143147delLEGTL） was detected in the family. The deletion, concerned with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 （CxS0）, was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes. MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel, indicating the deletion as a dominant-negative mutation, Conclusions： The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs.展开更多
目的明确1例先天性白内障患儿的遗传学病因,为该家系的临床诊断及遗传咨询提供依据。方法应用高通量测序技术对先证者进行遗传性眼病相关基因检测,筛选相关变异,采用Sanger测序法对先证者及家庭成员进行变异位点的验证。结果基因检测结...目的明确1例先天性白内障患儿的遗传学病因,为该家系的临床诊断及遗传咨询提供依据。方法应用高通量测序技术对先证者进行遗传性眼病相关基因检测,筛选相关变异,采用Sanger测序法对先证者及家庭成员进行变异位点的验证。结果基因检测结果显示先证者发生源自父母的GJA8基因c.855del和c.872dup的复合杂合变异,这两个变异均未见报道。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)遗传变异分类标准与指南,对这两个变异进行分析,GJA8基因c.855del判读为可能致病性(likely pathogenic)变异(PVS1_S+PM2+PP4),c.877dup为致病性(pathogenic)变异(PVS1_S+PM2+PM3+PP4)。结论GJA8基因c.855del和c.872dup的复合杂合变异可能为这例先天性白内障患儿的致病原因。展开更多
文摘Background： Congenital cataract （CC） is the leading cause of visual impairment or blindness in children worldwide. Because of highly genetic and clinical heterogeneity, a molecular diagnosis of the lens disease remains a challenge. Methods： In this study, we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure, pedigree validation, and molecular dynamics （MD） simulation. Results： A novel 15 bp deletion on GJA8 （c.426_440delGCTGGAGGGGACCCT or p. 143147delLEGTL） was detected in the family. The deletion, concerned with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 （CxS0）, was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes. MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel, indicating the deletion as a dominant-negative mutation, Conclusions： The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs.
文摘目的明确1例先天性白内障患儿的遗传学病因,为该家系的临床诊断及遗传咨询提供依据。方法应用高通量测序技术对先证者进行遗传性眼病相关基因检测,筛选相关变异,采用Sanger测序法对先证者及家庭成员进行变异位点的验证。结果基因检测结果显示先证者发生源自父母的GJA8基因c.855del和c.872dup的复合杂合变异,这两个变异均未见报道。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)遗传变异分类标准与指南,对这两个变异进行分析,GJA8基因c.855del判读为可能致病性(likely pathogenic)变异(PVS1_S+PM2+PP4),c.877dup为致病性(pathogenic)变异(PVS1_S+PM2+PM3+PP4)。结论GJA8基因c.855del和c.872dup的复合杂合变异可能为这例先天性白内障患儿的致病原因。
