Biallelic hypomorphic variants in CAD cause uridine‐responsive macrocytic anaemia with elevated haemoglobin‐A2

Abstract

SummaryBiallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de‐novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy‐50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin‐A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next‐generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.