本文在简要总结美国医学遗传学和基因组学学会(American College of Medical Genetics and Genomics,ACMG)判定规则的基础上,介绍了Varsome、Intervar、Franklin、AutoPVS1等常见的序列变异致病性解读网站和软件。这些软件对ACMG指南规...本文在简要总结美国医学遗传学和基因组学学会(American College of Medical Genetics and Genomics,ACMG)判定规则的基础上,介绍了Varsome、Intervar、Franklin、AutoPVS1等常见的序列变异致病性解读网站和软件。这些软件对ACMG指南规则中基于人群频率和生物信息学预测数据的规则能够进行很好的判读,而基于文献方面的规则需要手工判读。实验室和临床工作者合理使用自动化解读工具,可以提高对基因序列变异致病性判读的效率,确定临床患者的遗传学病因,建立临床症状和基因间的关系。展开更多
极长链酰基辅酶A脱氢酶缺乏症(very long chain Acyl-CoA dehydrogenase deficiency,VLCADD)是一种罕见的遗传病,特征是脂肪酸代谢受损,遵循常染色体隐性遗传。VLCADD主要是由脂肪酸β氧化中的必需酶极长链酰基辅酶A脱氢酶(very long ch...极长链酰基辅酶A脱氢酶缺乏症(very long chain Acyl-CoA dehydrogenase deficiency,VLCADD)是一种罕见的遗传病,特征是脂肪酸代谢受损,遵循常染色体隐性遗传。VLCADD主要是由脂肪酸β氧化中的必需酶极长链酰基辅酶A脱氢酶(very long chain acylCo A dehydrogenase,VLCAD)基因缺陷所致[1],以低酮性低血糖、心肌病、肝损伤和肌病为主要特征。展开更多
Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
文摘本文在简要总结美国医学遗传学和基因组学学会(American College of Medical Genetics and Genomics,ACMG)判定规则的基础上,介绍了Varsome、Intervar、Franklin、AutoPVS1等常见的序列变异致病性解读网站和软件。这些软件对ACMG指南规则中基于人群频率和生物信息学预测数据的规则能够进行很好的判读,而基于文献方面的规则需要手工判读。实验室和临床工作者合理使用自动化解读工具,可以提高对基因序列变异致病性判读的效率,确定临床患者的遗传学病因,建立临床症状和基因间的关系。
文摘极长链酰基辅酶A脱氢酶缺乏症(very long chain Acyl-CoA dehydrogenase deficiency,VLCADD)是一种罕见的遗传病,特征是脂肪酸代谢受损,遵循常染色体隐性遗传。VLCADD主要是由脂肪酸β氧化中的必需酶极长链酰基辅酶A脱氢酶(very long chain acylCo A dehydrogenase,VLCAD)基因缺陷所致[1],以低酮性低血糖、心肌病、肝损伤和肌病为主要特征。
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
