A proposed role for CDO1 in CNS development: Three children with rare missense variants and a neurological phenotype.

Cysteine dioxygenase type 1 (CDO1) encodes a non-heme iron dioxygenase, which is involved in cysteine metabolism. While CDO1 has been proposed to be involved in multiple physiological processes, an association with congenital disease has yet to be well defined. This study presents detailed clinical and molecular information on three individuals with overlapping neurological features. All three individuals were found to have rare, conserved, de novo variants clustered in a conserved region of the CDO1 gene with no alternative genetic etiology identified. Features present in all three individuals included electroencephalogram abnormality or seizure, movement abnormalities, hypertonia, encephalopathy, severe microcephaly (-4 SD below mean), growth failure, feeding difficulty, and abnormal brain morphology. Other common features included global developmental delay, sleep disturbance, contractures, cerebral palsy, hyper-reflexia, hearing loss, and hypoxic respiratory failure. This study provides evidence supporting an association between de novo CDO1 missense variants and human neurological disease.