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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.

项目总结