Expert curation of sequence variants in the proximal urea cycle genes

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.

Grant Number: 5U24HD108087-03
NIH Institute/Center: NIH
Principal Investigator: Ljubica Caldovic