Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder

Abstract

Purpose RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants. Methods We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2 , PDZ-GEF , and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. ..