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Eur J Hum Genet. 2019 Oct;27(10):1611-1618. doi: 10.1038/s41431-019-0462-x. Epub 2019 Jul 5.

De novo substitutions of TRPM3 cause intellectual disability and epilepsy.

Author information

1
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
2
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
3
Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
4
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
5
Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
6
University of South Florida, Tampa, FL, USA.
7
Nicklaus Children's Hospital, Miami, FL, USA.
8
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
9
Department of Pediatrics, Division of Genetics, Maine Medical Center, Portland, ME, USA.
10
GeneDx, Gaithersburg, MD, USA.
11
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
12
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada. mlines@cheo.on.ca.
13
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada. mlines@cheo.on.ca.

Abstract

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

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