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Intellectual disability

Gene: CAD

Green List (high evidence)

CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase)
EnsemblGeneIds (GRCh38): ENSG00000084774
EnsemblGeneIds (GRCh37): ENSG00000084774
OMIM: 114010, Gene2Phenotype
CAD is in 8 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: CAD identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.

CAD has also been reviewed Amber by Konstantinos Varvagiannis. 5 patients from 4 families in total (1 patient from PMID:25678555 and 4 more patients from 28007989) 2 families have the same variant and are Serbian-Roma in descent, however there are sufficient indinviduals to rate as Green. All individuals reported to have developmental delay which preceded the onset of seizures. CAD has also been reviewed for the Genetic epilepsy syndromes panel.

Confirmed DD-G2P gene for Uridine-responsive epileptic encephalopathy. Therefore treatable tag has been added.
Created: 16 May 2019, 11:10 a.m. | Last Modified: 17 Jul 2019, 9:58 a.m.
Panel Version: 0.200

Konstantinos Varvagiannis (Other)

I don't know

Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457.

Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary).

The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset.

CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis.

In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway.

CAD mutations have previously been studied in other model organisms.

Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes.

The disorder appears to be amenable to dietary intervention (uridine supplementation).

CAD is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID panel as amber or green.
Sources: Literature
Created: 4 Dec 2018, 11:59 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Epileptic encephalopathy, early infantile, 50 - MIM 616457


Variants in this GENE are reported as part of current diagnostic practice


Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Green
  • Literature
  • Epileptic encephalopathy, early infantile, 50 - MIM 616457
Clinvar variants
Variants in CAD
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to CAD. Added phenotypes Epileptic encephalopathy, early infantile, 50 - MIM 616457 for gene: CAD Publications for gene CAD were changed from 25678555; 28007989 to 25678555; 28007989; 30914295 Rating Changed from No List (delete) to Green List (high evidence)

4 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: CAD was added gene: CAD was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAD were set to 25678555; 28007989 Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50 - MIM 616457 Penetrance for gene: CAD were set to Complete Review for gene: CAD was set to AMBER gene: CAD was marked as current diagnostic