Bi-allelic variants in <i>CHKA</i> cause a neurodevelopmental disorder with epilepsy and microcephaly

Abstract The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy ( CHKB ), bone abnormalities and cone-rod dystrophy ( PCYT1A ), and spastic paraplegia ( PCYT2, SELENOI ). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these…