Expert curation of sequence variants in the proximal urea cycle genes

项目摘要 尿素循环障碍（UCD）是一种先天性代谢缺陷，大约每35，000人中就有1人受到影响， 是由八个尿素循环基因中的一个基因缺陷引起的。八个基因中任何一个的遗传缺陷 可引起高氨血症，高氨血症是疾病病理生理学的主要因素， 神经损伤，范围从轻度执行功能缺陷到严重的智力和 发育障碍甚至死亡高氨血症最明显的是缺乏第一 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 （CPS 1）和鸟氨酸转氨甲酰酶（OTC）。由于神经心理学的广泛性 与UCD相关的后遗症，了解其分子基础并改善其早期诊断， NICHD的高优先级研究。此应用程序来自现有的UCD变体策展专家小组 （VCEP）向ClinGen的序列变异解释提交了OTC特异性变异分类规则 工作组进行审查，并一直在制定NAGS和CPS 1特定的变体分类规则。我们 正在寻求对近1，300种OTC、NAGS和CPS 1临床可行变体的专家策展支持 这些数据已经被保存在公共数据库中，并在文献中报道。建立一个全面、 OTC、NAGS和CPS 1变异体的专业策划目录对于这三种变异体的准确诊断至关重要 UCD。 我们已经组建了一个VCEP，其中包括经验丰富的遗传咨询师和遗传学学员作为变体 策展人和尿素循环障碍联盟（UCDC）的成员作为专家评审员。UCDC是一个 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 照顾患有UCD的患者。在目标1中，我们将指定OTC、NAGS和 ClinVar中的CPS 1变体、其他公共来源的疾病相关序列变体和已发表病例 报道变体将按以下顺序进行策划：功能完全丧失（空）变体，错义 影响酶功能关键残基的变异，在多个先证者中鉴定的变异，NAGS和 CPS 1变体与现有致病性变体的反式，影响与现有变体相同残基的变体 致病性错义变体，然后是所有其他错义变体。在目标2中，我们将每年审查文献 关于NAGS、CPS 1或OTC缺乏症患者的新报告以及关于 人口众多。我们将利用新证据重新评估有潜力的变体 重新分类（例如，不确定的重要性到可能的致病性或致病性，或可能的良性到良性）。 OTC、NAGS和CPS 1变体的专家分类将改善以下疾病的诊断和临床可操作性： 与疾病有明确关系的变异。这将有利于患者，治疗医生和诊断 laboratories.

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.