PROJECT SUMMARY
Ornithine transcarbamylase (OTC) deficiency and N-acetylglutamate synthetase (NAGS) deficiency are inborn
errors of metabolism that are caused by genetic defects in the urea cycle genes OTC and NAGS. Genetic
defects in these genes can cause hyperammonemia, brain edema, and neurological injury that ranges from
mild executive functioning deficits to profound intellectual and developmental disabilities and even death. OTC
deficiency is the most common and the only X-linked urea cycle disorder (UCD) whereas NAGS deficiency is
the only UCD that can be effectively treated with drug monotherapy. Because of the broad spectrum of
neuropsychological sequelae associated with OTC and NAGS deficiencies, understanding their molecular
basis and improving their early diagnosis are among NICHD high research priorities.
OTC and NAGS deficiencies are most often diagnosed by DNA testing because biochemical testing may not
always sufficiently differentiate between different UCDs. DNA sequence variants identified in these genes are
not always deleterious, and the current ACMG (American College of Medical Genetics and Genomics) and
AMP (Association for Molecular Pathology) standardized framework for the interpretation and classification of
DNA variants relies on published or publicly available computational, functional, segregation, population, allelic
and clinical data in order to classify a variant. Because such publicly available data is limited, the majority of
known sequence variants in the urea cycle genes OTC and NAGS would currently be classified as variants of
uncertain significance. Correct classification of such variants is necessary 1) to accurately diagnose and treat
these disorders 2) for reproductive counseling of affected patients and their relatives and 3) to inform the
design of diagnostic eligibility criteria for clinical trials of these disorders.
To permit the correct assignment of pathogenicity of known OTC and NAGS variants by clinical diagnostic
laboratories and by the NIH-supported ClinGen UCD Variant Curation Expert Panel, this project seeks to
leverage the combined data from 3 sources: 1) the largest natural history study of UCDs conducted by the
NICHD-funded UCD Consortium, 2) the largest US clinical UCD expert center, Children’s National Hospital and
3) the largest private OTC and NAGS dataset from the legacy Tuchman lab. The Tuchman lab was an
academic laboratory that prior to 2012 served as the US reference center for clinical OTC and NAGS
sequencing. The legacy database of this lab contains over 20 years of variant and unpublished clinical data
from US patients with OTC and NAGS and their relatives. We propose to combine and disambiguate
anonymized data from these 3 complementary datasets, and publish the data that fulfill segregation,
population, allelic and clinical variant curation criteria. For each OTC and NAGS variant, we intend to submit
these data into ClinVar, a publicly accessible database that aggregates information about genetic variants.
