Alagille syndrome mutation update: Comprehensive overview of JAG1 JAG1 and NOTCH2 NOTCH2 mutation frequencies and insight into missense variant classification

Gilbert Melissa A.; Bauer Robert C.; Rajagopalan Ramakrishnan; Grochowski Christopher M.; Chao Grace; McEldrew Deborah; Nassur James A.; Rand Elizabeth B.; Krock Bryan L.; Kamath Binita M.; Krantz Ian D.; Piccoli David A.; Loomes Kathleen M.; Spinner Nancy B.

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Alagille syndrome mutation update: Comprehensive overview of JAG1 JAG1 and NOTCH2 NOTCH2 mutation frequencies and insight into missense variant classification

机译：Alagille综合征突变更新：JAG1 JAG1和Notch2突变频率的全面概述和洞察密封变种分类

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Abstract Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 ( JAG1 ), but also by variants in NOTCH2 . The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single‐center study, which includes 401 probands and 111 affected family members amassed over a 27‐year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.

机译：摘要Alagille综合征是一种常染色体显性疾病，其具有主要由锯齿状1（JAG1）中的致病变体引起的功能障碍Notch信号传导的已知分子病因，但也由Notch2中的变体。大多数JAG1变体导致功能丧失，但疾病也归因于较小的密码变异。相反，大多数Notch2变体都是畸形的，但已经描述了较少的这些变体。此外，还有一小组患者在没有致病变体的情况下具有明显的临床表型。在这里，我们目录是我们的单中心研究，其中包括401个证据和111个受影响的家庭成员，在27年内大通，为JAG1和Notch2提供更新的突变频率，以及九个麦克信变种的功能验证。将我们的86个新型JAG1和三种新颖的Notch2变体组合在一起与先前发表的数据（总共713种变种），我们为Alagille综合征提供了最全面的致病变体概述。使用此数据集，我们开发了新的指导，以帮助jag1密码变体的分类。最后，我们报告临床上一致的病例，其中尚未确定分子病因，并讨论新型变异发现中下一代测序方法的潜力。

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《Human mutation》 |2019年第12期|共24页
作者
Gilbert Melissa A.; Bauer Robert C.; Rajagopalan Ramakrishnan; Grochowski Christopher M.; Chao Grace; McEldrew Deborah; Nassur James A.; Rand Elizabeth B.; Krock Bryan L.; Kamath Binita M.; Krantz Ian D.; Piccoli David A.; Loomes Kathleen M.; Spinner Nancy B.;
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作者单位

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Pediatric Gastroenterology Hepatology and Nutrition Department of Pediatrics;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

Division of Gastroenterology Hepatology and Nutrition Department of PediatricsHospital for Sick;

Division of Human Genetics Roberts Individualized Medical Genetics CenterChildren's Hospital of;

Division of Pediatric Gastroenterology Hepatology and Nutrition Department of Pediatrics;

Division of Pediatric Gastroenterology Hepatology and Nutrition Department of Pediatrics;

Division of Genomic Diagnostics Department of Pathology and Laboratory Medicine Children's;

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原文格式 PDF
正文语种 eng
中图分类医学遗传学;
关键词
Alagille syndrome; JAG1; liver; NOTCH2;

机译：Alagille综合症;Jag1;肝脏;Notch2;

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专利

1. Alagille syndrome mutation update: Comprehensive overview of JAG1 JAG1 and NOTCH2 NOTCH2 mutation frequencies and insight into missense variant classification [J] . Gilbert Melissa A., Bauer Robert C., Rajagopalan Ramakrishnan, Human mutation . 2019,第12期

机译：Alagille综合征突变更新：JAG1 JAG1和Notch2突变频率的全面概述和洞察密封变种分类
2. Exome Sequencing Reveals Compound Heterozygous Mutations in ATP8B1 in a JAG1/NOTCH2 Mutation-Negative Patient with Clinically Diagnosed Alagille Syndrome [J] . Grochowski Christopher M., Rajagopalan Ramakrishnan, Falsey Alexandra M., American journal of medical genetics, Part A . 2015,第4期

机译：外显子组测序揭示了JAG1 / NOTCH2突变阴性临床诊断为Alagille综合征的患者中ATP8B1的复合杂合突变。
3. Screening for Alagille Syndrome Mutations in the JAG1 and NOTCH2 Genes Using Denaturing High-Performance Liquid Chromatography [J] . HAZUKI SAMEJIMA, CHIHARU TORII, RIKA KOSAKI, Genetic Testing . 2007,第3期

机译：使用变性高效液相色谱法筛选JAG1和NOTCH2基因中的Alagille综合征突变
4. Mechanistic Insights to Pro-arrhythmogenesis of Short QT Syndrome Associated with V307L Gene Mutation in Potassium Channel (IKs) [C] . Henggui Zhang, Sanjay Kharche, Jules C. Hancox The 12th world multi-conference on systemics, cybernetics and informatics : Proceedings . 2008

机译：钾通道（IKs）中V307L基因突变相关的短QT综合征促心律失常的机制性见解。
5. Novel Heterozygous Mutations in JAG1 and NOTCH2 Genes in a Neonatal Patient with Alagille Syndrome [O] . Alisa Brennan, Anil Kesavan 2017

机译：新型Alagille综合征患者JAG1和NOTCH2基因的新型杂合突变。
6. Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome [O] . J. J.D. Morrissette 2001

机译：Alagille综合征在Alagily综合征中有缺陷的细胞内运输和Jag1畸形突变的处理

Alagille syndrome mutation update: Comprehensive overview of JAG1 JAG1 and NOTCH2 NOTCH2 mutation frequencies and insight into missense variant classification

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