De novo substitutions of TRPM3 cause intellectual disability and epilepsy

David A Dyment,Cecilie F Rustad,Parul Jayakar,Sara Ellingwood,Koen Van Gassen,Kristian Tveten,A Micheil Innes,Marwan Shinawi,Kirsty Mcwalter,Matthew A Lines,Rosemarie Smith,Paulien A Terhal,Christopher Griffith

doi:10.1038/s41431-019-0462-x

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.

Highlights

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability (ID)
We present eight individuals with a neurodevelopmental phenotype comprising ID, hypotonia, epilepsy, and a recognizable craniofacial gestalt; exome sequencing showed de novo substitutions of a Transient receptor potential (TRP) channel, TRPM3, in each
We propose that de novo substitutions of TRPM3 are a cause of ID and epilepsy

Summary

Introduction

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability (ID). Rare nonsynonymous coding variants in genes encoding ion channels, cell-surface receptors, and other neuronally expressed proteins are identifiable in one about quarter of affected individuals [1,2,3]. Most identified variants in individuals with DEE are in-frame, de novo, and recurrent across unrelated kindreds [2]. Transient receptor potential (TRP) channels are a superfamily of gated cation channels sensitive to a variety of physical and chemical stimuli [4]. Seven subfamilies are recognized [5]. TRP channels are implicated in several Mendelian disorders, including polycystic kidney disease (OMIM #613095), mucolipidosis type IV (#252650), amyotrophic lateral sclerosis–dementia–parkinsonism

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