Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

阿拉吉尔综合征肝病严重程度的基因修饰

• 批准号: 8502652
• 负责人: Nancy Bettina Spinner
• 金额: $ 59.85万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502652
• 关键词: Affect; Alagille Syndrome; Attention; Biochemical; Candidate Disease Gene; Cardiac; Cholestasis; Clinical; Collaborations; Copy Number Polymorphism; Databases; Development; Disease; Disease Progression; Enzymes; Family; Genes; Genetic; Genomics; Housing; Individual; International; Intrahepatic bile duct; Italy; Laboratories; Lead; Liver; Liver diseases; Methodology; Morbidity - disease rate; Mutation; Notch Signaling Pathway; Online Mendelian Inheritance In Man; Pathway interactions; Patients; Pattern; Poland; Records; Recruitment Activity; Research Personnel; Severities; Severity of illness; Signaling Pathway Gene; Spain; Staging; Stratification; System; Techniques; Testing; Transplantation; Variant; base; clinically relevant; cohort; disease phenotype; genome wide association study; genome-wide; improved; kidney vascular structure; liver injury; liver transplantation; malformation; mortality; outcome forecast

DESCRIPTION (provided by applicant): This is a proposal to identify clinically relevant modifiers of the severity of hepatic disease in patients with Alagille Syndrome (AGS) AGS is an autosomal dominant, multi-system, variably expressed disorder caused by mutations in one of two Notch Signaling Pathway genes. Mutations in Jagged1 (JAG1) are found in 95% of patients and mutations in Notch2 in less than 1%. AGS causes significant morbidity associated with liver, cardiac, renal and vascular malformations. The liver disease in AGS is characterized pathologically by intrahepatic bile duct paucity, with resulting cholestasis, and ranges from very mild (sub-clinical with only biochemical abnormalities of liver enzymes) to severe, in which case liver damage is extensive and a transplant is required. Mortality due to liver disease is about 5%. The highly variable expressivity is consistent with the presence of modifying factors that contribute to expressivity. We hypothesize that there are genetic modifiers of the severity of liver disease. We propose a multi-pronged approach to the identification of these genetic modifiers. Using our well-characterized cohort of patients with AGS and JAG1 mutations, we will compare patients with mild liver disease to patients with severe liver disease to look for evidence of genomic differences between the two groups. Recognizing the importance of attaining adequate power for the proposed studies, we will aggressively recruit additional patients. We will use multiple techniques to look for genetic differences between the patients with mild liver disease versus those with severe liver disease. We will test for association of copy number variants with liver disease severity. We will carry out a genome-wide association study using random tagSNPs and SNPs in specific genomic regions (candidate genes). We anticipate that identification of modifying factors for liver disease severity will have implications beyond Alagille syndrome patients, and may point to modifiers of liver disease severity in other disorders associated with cholestasis.

描述（由申请人提供）：

项目成果

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome.

外显子组测序揭示了一名临床诊断为 Alagille 综合征的 JAG1/NOTCH2 突变阴性患者的 ATP8B1 复合杂合突变。

• DOI: 10.1002/ajmg.a.36946
• 发表时间: 2015
• 期刊: American journal of medical genetics. Part A
• 作者: Grochowski,ChristopherM;Rajagopalan,Ramakrishnan;Falsey,AlexandraM;Loomes,KathleenM;Piccoli,DavidA;Krantz,IanD;Devoto,Marcella;Spinner,NancyB
• 通讯作者: Spinner,NancyB

NOTCH2 mutations in Alagille syndrome.

• DOI: 10.1136/jmedgenet-2011-100544
• 发表时间: 2012-02
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Kamath BM;Bauer RC;Loomes KM;Chao G;Gerfen J;Hutchinson A;Hardikar W;Hirschfield G;Jara P;Krantz ID;Lapunzina P;Leonard L;Ling S;Ng VL;Hoang PL;Piccoli DA;Spinner NB
• 通讯作者: Spinner NB

Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features.

• DOI: 10.1002/ajmg.a.35255
• 发表时间: 2012-05
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Lin, Henry C.;Phuc Le Hoang;Hutchinson, Anne;Chao, Grace;Gerfen, Jennifer;Loomes, Kathleen M.;Krantz, Ian;Kamath, Binita M.;Spinner, Nancy B.
• 通讯作者: Spinner, Nancy B.

Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.

基因组测序增加了临床诊断的阿拉吉尔综合征患者的诊断产量，其先前测试结果为阴性。

• DOI: 10.1038/s41436-020-00989-8
• 发表时间: 2021-03
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Rajagopalan R;Gilbert MA;McEldrew DA;Nassur JA;Loomes KM;Piccoli DA;Krantz ID;Conlin LK;Spinner NB
• 通讯作者: Spinner NB