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TRPM3-Associated Neurodevelopmental Disorder
TRPM3-associated disorder is a rare, predominantly de novo, autosomal dominant condition caused by pathogenic gain-of-function variants in the TRPM3gene located on chromosome 9. TRPM3 is a member of the transient receptor potential (TRP) superfamily of ion channels, and forms a calcium- and sodium-permeable cation channel gated by increasing temperature and by ligands such as the neurosteroid pregnenolone sulphate. In peripheral sensory neurons such as those in the dorsal root ganglion and trigeminal ganglion, TRPM3 acts as a detector of noxious heat, and is involved in acute and chronic pain signaling. TRPM3 is also broadly expressed in the central nervous system, particularly in the thalamus, hippocampus, cerebral cortex, and cerebellum, where it may contribute to neuronal excitability and intracellular calcium signaling. To date, the exact biological role of the TRPM3 channel in the central nervous system remains unknown.

Pathogenic mutations in TRPM3are very rare, with currently less than 100 reported cases world-wide. The disease-causing TRPM3variants cause a gain-of-function, and are associated with a spectrum of neurological and neurodevelopmental phenotypes, mostly involving developmental delay and intellectual disability, as well as epilepsy or other EEG abnormalities. Almost all affected individuals have a de novopathogenic variant, although inheritance through a mildly affected parent carrying the variant has been reported.