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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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