Expert curation of sequence variants in the proximal urea cycle genes

近端尿素循环基因序列变异的专家管理

基本信息

批准号：
10630560
负责人：
Nicholas Ah Mew
金额：
$ 40.04万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630560
关键词：
Acceleration Acute Affect Alleles Ammonia Archives Benign Birth Brain Brain Death Brain Edema Brain Injuries Carbamyl Phosphate Case Study Catalogs Cessation of life Child Classification ClinVar Clinical Collaborations Coma Conflict (Psychology)DNA sequencing Data Databases Dedications Deposition Developmental Disabilities Diagnosis Diagnostic Disease Early Diagnosis Enzymes Executive Dysfunction Foundations Functional disorder Genes Genetic Health Professional Hyperammonemia Inborn Errors of Metabolism Incidence Individual Information Systems Intellectual functioning disability International Laboratories Life Ligase Link Literature Methods Mitochondria Molecular Molecular Diagnosis Molecular Genetics Mutation N acetyl L glutamate N-carbamylglutamate National Institute of Child Health and Human Development Natural History Nervous System Trauma Neurocognitive Deficit Neurologic Symptoms Neuropsychology Organ Ornithine Carbamoyltransferase Ornithine carbamoyltransferase deficiency Pathogenicity Patient Care Patients Persons Physicians Population Production Publishing Recommendation Registries Reporting Research Research Priority Review Literature Severity of illness Source Subgroup Test Result Toxic effect Urea Urea cycle disorders Variant accurate diagnosis actionable mutation clinical care clinically actionable clinically significant cost disease classification experience falls genetic counselor genetic variant improved inborn urea cycle disorder loss of function member next generation sequencing proband public database rare genetic disorder screening urea cycle variant of unknown significance willingness working group

项目摘要

PROJECT SUMMARY Urea cycle disorders (UCDs) are inborn errors of metabolism that affect approximately 1 in 35,000 people and are caused by genetic defects in one of the eight urea cycle genes. Genetic defects in any of the eight genes can cause hyperammonemia which is the primary contributor to disease pathophysiology, leading to neurological injury that ranges from mild executive functioning deficits to profound intellectual and developmental disabilities and even death. Hyperammonemia is most pronounced in deficiencies of the first three enzymes of the urea cycle: N-acetylglutamate synthase (NAGS), carbamylglutamate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC). Because of the broad spectrum of neuropsychological sequelae associated with UCDs, understanding their molecular basis and improving their early diagnosis are among NICHD high research priorities. This application is from an existing UCD variant curation expert panel (VCEP), which submitted OTC specific variant classification rules to ClinGen’s Sequence Variant Interpretation Working Group for review and has been developing NAGS and CPS1 specific variant classification rules. We are seeking support for expert curation of almost 1,300 OTC, NAGS and CPS1 clinically actionable variants that have been deposited in public databases and reported in the literature. Establishment of a comprehensive, expertly-curated catalogue of OTC, NAGS and CPS1 variants is essential for accurate diagnosis of the three UCDs. We have assembled a VCEP that includes experienced genetic counselors and genetics trainees as variant curators, and members of the Urea Cycle Disorders Consortium (UCDC) as expert reviewers. UCDC is an international research collaboration of health professionals with specialized expertise in diagnosis and clinical care of patients with UCDs. In Aim 1, we will assign expert-reviewed clinical significance to OTC, NAGS and CPS1 variants in ClinVar, other public sources of disease associated sequence variants, and in published case reports. Variant will be curated in the following order: complete loss of function (null) variants, missense variants affecting residues critical for enzyme function, variants identified in multiple probands, NAGS and CPS1 variants in trans with existing pathogenic variants, variants affecting the same residues as existing pathogenic missense variants, then all other missense variants. In Aim 2, we will annually review the literature for new reports of patients with NAGS, CPS1 or OTC deficiency and new data regarding sequence variation in large populations. We will utilize the new evidence for reassessment of variants with potential for reclassification (e.g., uncertain significance to likely pathogenic or pathogenic, or likely benign to benign). Expert classification of OTC, NAGS and CPS1 variants will improve diagnosis and clinical actionability for variants with clear relationship with the disease. This will benefit patients, treating physicians and diagnostic laboratories.

项目概要尿素循环障碍 (UCD) 是一种先天性代谢缺陷，影响大约三万五千分之一的人，是由八个尿素循环基因之一的遗传缺陷引起的。八个基因中任何一个的遗传缺陷。可引起高氨血症，这是疾病病理生理学的主要原因，导致神经损伤，范围从轻微的执行功能缺陷到严重的智力和发育障碍甚至死亡在第一种缺乏中最为明显。尿素循环的三种酶：N-乙酰谷氨酸合成酶 (NAGS)、氨甲酰谷氨酸合成酶 1 （CPS1）和鸟氨酸转氨甲酰酶（OTC）由于神经心理学的广谱性。与 UCD 相关的后遗症，了解其分子基础并改善其早期诊断是该应用程序来自现有的 UCD 变异管理专家小组。 (VCEP)，向 ClinGen 的序列变异解释提交了 OTC 特定变异分类规则工作组一直在进行审查并制定NAGS和CPS1的具体变体分类规则。正在寻求对近 1,300 个 OTC、NAGS 和 CPS1 临床可行变体的专家管理支持已存入公共数据库并在文献中报告。专家整理的 OTC、NAGS 和 CPS1 变异目录对于准确诊断这三种变异至关重要都柏林大学。我们组建了一个 VCEP，其中包括经验丰富的遗传咨询师和遗传学实习生作为变体策展人以及尿素循环障碍联盟 (UCDC) 的成员作为专家评审员。具有诊断和临床专业知识的卫生专业人员的国际研究合作在目标 1 中，我们将为 OTC、NAGS 和 NAGS 赋予专家评审的临床意义。 ClinVar 中的 CPS1 变异、其他公共疾病来源相关的序列变异以及已发表的病例变体将按以下顺序编译：功能完全丧失（空）变体、错义。影响对酶功能至关重要的残基的变异，在多个先证者中鉴定的变异，NAGS 和 CPS1变异体与现有致病变异体反式变异，变异体影响与现有致病变异体相同的残基致病性错义变异，然后是所有其他错义变异在目标 2 中，我们将每年回顾文献。 NAGS、CPS1 或 OTC 缺陷患者的新报告以及有关序列变异的新数据我们将利用新的证据来重新评估具有潜力的变异。重新分类（例如，对可能致病或致病的不确定意义，或对可能良性的不确定意义）。 OTC、NAGS 和 CPS1 变异的专家分类将提高诊断和临床可操作性与疾病有明确关系的变异体这将使患者、治疗医生和诊断受益。实验室。