Clinical Domain Working Groups

The urea cycle disorders (UCDs) comprise a group of genetic disorders impairing the urea cycle, which is responsible for the conversion of ammonia to urea for urinary excretion.  In the absence of functional urea cycle, ammonia can accumulate in the body and lead to severe clinical consequences including lethargy, poor feeding, vomiting, and encephalopathy, coma, and death.  Other UCDs not associated with acute hyperammonemia may present with clinical phenotypes including neurological or psychiatric symptoms, behavioral problems, lethargy, psychosis, and encephalopathy.

There are eight genes in the urea cycle, and they can be divided into three groups; proximal urea cycle (CPS1, NAGS, OTC), distal urea cycle (ASS1, ASL, ARG1); and transporters (SLC25A13, SLC25A15).  The UCD Expert Panel members have grouped these into Tier 1 (proximal urea cycle), Tier 2 (distal urea cycle), and Tier 3 (transporters) for variant curation purposes.

Tier 1 genes are highest priority for variant curation, as they encompass the earliest onset and most severe disorders of the urea cycle.  The proximal UCDs are characterized by severe and often fatal neonatal onset disease with clinical phenotypes including feeding difficulties, neonatal hyperammonemia, lethargy proceeding to coma and death.  Individuals with later onset milder disease have also been reported.  OTC is X-linked. Penetrance in females with pathogenic variants in OTC is estimated to be between 20-30% and is influenced by the pattern of X-inactivation in hepatocytes. OTC deficiency is the result of a pathogenic variant in the X-Linked Ornithine transcarbamylase gene [OTC; MIM#300461].  OTC Deficiency is the most common UCD, with an estimated worldwide incidence of 1/50,000.  Given its severe neonatal presentation and significant morbidity and mortality risks, OTC was added to the list of reportable ACMG Secondary Findings v2.0 (Kalia, 2016) and is present on many Carrier Screening Panels, making it a high priority for a concerted effort to deposit well curated variants in ClinVar.

After the Tier 1 genes are complete, we will proceed with Tier 2 and Tier 3 genes accordingly.