CAD

protein-coding

carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, the group of Glutamine amidotransferase class 1 domain containing

Gene summary

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

MANE transcript

NM_004341.5

Inheritance

ClinVar variants

P:111U:742B:847

Top phenotype

Developmental and epileptic encephalopathy 50

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr2:27,217,369-27,243,943

External References & Databases

Ensembl (ENSG00000084774)

Transcript & Mutation Effects

hg38 • Region Span ~26.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 50DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014647

Submitter: G2P

developmental and epileptic encephalopathy, 50MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014647

Submitter: Illumina

developmental and epileptic encephalopathy, 50SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014647

Submitter: Orphanet

developmental and epileptic encephalopathy, 50DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014647

Submitter: ClinGen

CAD was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2015 (Ng et al., PMID 25678555). Thirteen variants (missense, nonsense, frameshift, splice site) that have been reported in 8 probands in 5 publications (PMIDs 25678555, 28007989, 32117025, 32820246, 29396846) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Patients have a range of symptoms, including early-onset epilepsy, developmental delay, developmental regression, and anemia. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by the biochemical function of CAD, which is involved in de novo synthesis of uridine 5-monophosphate (UMP), the precursor of pyrimidine nucleotides (PMID 34288185). In vitro assays support a defect in this pathway and supplementation of uridine has been shown to improve the clinical outcome of patients with variants in CAD (PMIDs 25678555, 32461667). Studies in zebrafish and Drosophila also support a role in pyrimidine biosynthesis (PMIDs 15937129, 5004701). In summary, there is definitive evidence supporting the relationship between CAD and autosomal recessive developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

developmental and epileptic encephalopathy, 50STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014647

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 50AR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic; Renal

Intervention: Biochemical; Gastrointestinal; Renal

Rationale: Medical management (with uridine) has been described as beneficial; Among other manifestations, the conditions has been described as including renal tubular acidosis, which has been reported as amenable to treatment (eg, with citrate); The condition has been reported as including pan-disaccharidase deficiency, which was treated (with probiotics and digestive enzymes)

Refs: 25678555; 28007989

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAD variants in ClinVar

11 Conditions Cataloged

not providedTotal: 2159

Inborn genetic diseasesTotal: 245

not specifiedTotal: 141

Developmental and epileptic encephalopathy, 50Total: 96

CAD-related disorderTotal: 61

Infantile epileptic dyskinetic encephalopathyTotal: 8

Coronary artery disease, autosomal dominant 2Total: 4

Meniere diseaseTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004341.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			25 clinvar	819 clinvar	9 clinvar	853
missense	2 clinvar	12 clinvar	700 clinvar	19 clinvar		733
nonsense	24 clinvar	3 clinvar	4 clinvar			31
start loss						0
frameshift	34 clinvar	11 clinvar	4 clinvar			49
splice donor/acceptor (+/-2bp)	1 clinvar	24 clinvar	9 clinvar			34
Total	61	50	742	838	9	1700

Highest pathogenic variant AF is 0.00022201735

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004341.5	RefSeq	NP_004332.2	44	MANE Select
ENST00000264705.9	Ensembl	ENSP00000264705.3	44	MANE Select
NM_001306079.2	RefSeq	NP_001293008.1	43	Standard
ENST00000403525.5	Ensembl	ENSP00000384510.1	43	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cad	Danio rerio	Structure: blood vessel endothelial cell Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

cad

Danio rerio

Structure: blood vessel endothelial cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Pyrimidine metabolism - Homo sapiens (human)
2-Hydroxyglutric Aciduria (D And L Form)
Pyrimidine Metabolism
Hypoacetylaspartia

Biological Process

liver development
'de novo' pyrimidine nucleobase biosynthetic process
UTP biosynthetic process
glutamine metabolic process
nitrogen compound metabolic process

Molecular Function

aspartate carbamoyltransferase activity
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
dihydroorotase activity
protein kinase activity
ATP binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264705
Coding exons: 44
Length: 26554
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.34	913	1.36e+3	0.670	0.0000865	14317
Missense (PolyPhen)		289	572.9	0.50445		5999
Synonymous	-0.930	570	542	1.05	0.0000331	4754
Loss of Function	8.09	19	111	0.171	0.00000632	1170

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase). {ECO:0000269|PubMed:24332717}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 50 (EIEE50) [MIM:616457]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE50 is an autosomal recessive, progressive disease with onset in infancy and favorable response to treatment with oral uridine. {ECO:0000269|PubMed:25678555, ECO:0000269|PubMed:28087732}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.132

Intolerance Scores

RVIS EVS: -3.84
RVIS percentile EVS: 0.23

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium