Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia

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, Shane McKee, Jinfon Ong, Hana Zibdeh-LoughFrederic 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*, TUDP Study Group

*Corresponding author for this work


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.

Original languageEnglish
JournalAmerican Journal of Medical Genetics. Part A
Issue number6
Pages (from-to)1667-1675
Number of pages9
Publication statusPublished - Jun 2022


  • Child
  • Developmental Disabilities/genetics
  • Epilepsy
  • Humans
  • Infant, Newborn
  • Infant, Newborn, Diseases
  • Intellectual Disability/genetics
  • Muscle Hypotonia/genetics
  • Mutation, Missense
  • TRPM Cation Channels/genetics
  • Whole Exome Sequencing


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