De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features

Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder. Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB. Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFBR104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton. The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.