TY - JOUR
T1 - De novo substitutions of TRPM3 cause intellectual disability and epilepsy
AU - Dyment, David A.
AU - Terhal, Paulien A.
AU - Rustad, Cecilie F.
AU - Tveten, Kristian
AU - Griffith, Christopher
AU - Jayakar, Parul
AU - Shinawi, Marwan
AU - Ellingwood, Sara
AU - Smith, Rosemarie
AU - van Gassen, Koen
AU - McWalter, Kirsty
AU - Innes, A. Micheil
AU - Lines, Matthew A.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068459354&partnerID=8YFLogxK
U2 - 10.1038/s41431-019-0462-x
DO - 10.1038/s41431-019-0462-x
M3 - Article
C2 - 31278393
AN - SCOPUS:85068459354
VL - 27
SP - 1611
EP - 1618
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 10
ER -