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TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic-clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate-severe intellectual disability with, or without, childhood-onset epilepsy. © 2022 Wiley Periodicals LLC.


Matthew A Lines, Paula Goldenberg, Ashley Wong, Siddharth Srivastava, Allan Bayat, Hanne Hove, Helena Gásdal Karstensen, Kwame Anyane-Yeboa, Jun Liao, Nan Jiang, Alison May, Edwin Guzman, Manuela Morleo, Stefano D'Arrigo, Claudia Ciaccio, Chiara Pantaleoni, Raffaele Castello, TUDP Study Group, Shane McKee, Jinfon Ong, Hana Zibdeh-Lough, Frederic Tran-Mau-Them, Anna Gerasimenko, Delphine Heron, Boris Keren, Henri Margot, Jean-Madeleine de Sainte Agathe, Lydie Burglen, Thomas Voets, Joris Vriens, A Micheil Innes, David A Dyment. Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia. American journal of medical genetics. Part A. 2022 Jun;188(6):1667-1675

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PMID: 35146895

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