Bi-allelic variants in the PRMT9 gene that abolish the function of the encoded protein give rise to a neurodevelopmental disorder with autosomal recessive inheritance. A recent study published in the American Journal of Human Genetics reported 35 affected individuals from 26 families and identified 26 distinct disease-causing PRMT9 variants. The patients presented with a syndrome of variable severity that included global developmental delay, learning difficulties, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia, along with additional features such as facial anomalies. A knockout zebrafish model displayed abnormal social behavior, and functional experiments in patient-derived cells provided new insights into the biological role of PRMT9.

PRMT9 (protein arginine methyltransferase 9) is one of nine members of a protein family whose main function is to catalyze methylation of arginine residues on histones and a range of other substrate proteins. Because PRMT9 interacts with the splicing factor SF3B2/SAP145, it has previously been implicated in neurodevelopment and the regulation of alternative splicing. The new study now offers direct evidence that PRMT9 plays an important role in the formation of primary cilia and in the modulation of cilia-dependent signaling pathways. Cilia are hair-like protrusions on the cell surface that function as antennae, sensing chemical and mechanical cues from the environment and transmitting these signals into the cell. During embryonic development, cilia-mediated signaling contributes to body axis formation and organ patterning, including the development of the heart, brain, and skeleton. Disruption of ciliogenesis can lead to a broad spectrum of human diseases.