Early onset or syndromic epilepsy

Gene: TRPM3

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Comment on list classification: This gene will be flagged for review at the next GMS panel update, in view of recently published functional data and expert reviews.

Created: 15 Oct 2020, 1:33 p.m. | Last Modified: 15 Oct 2020, 1:33 p.m.

Panel Version: 2.173

Currently rated VUS in OMIM for this phenotype, but entry is only based on PMID:31278393 and does not include the publications outlined below (last edited on 11/02/2020). Now also a probable gene for TRPM3-related developmental disorder in Gen2Phen.

- Two recent studies (PMID:32343227 and 32427099) have published data on the functional consequences of the p.Pro937Gln and p.Val837Met variants of TRPM3. Both studies demonstrated that the variants lead to significant gain-of-channel function, however each variant had distinct mechanisms of increased channel activity.

- de Sainte Agathe et al. (2020, PMID: 32439617) - report an 8th patient with the same recurrent de novo p.Val837Met missense of TRPM3 found in 7/8 cases from the previous study. This individual presented early with neurodevelopmental delay, ID and global hypotonia, consistent with previous reports. However, at 5-years-old she had not presented seizures and EEG performed at 13 months and 3 years were found to be normal.

Created: 15 Oct 2020, 1:30 p.m. | Last Modified: 15 Oct 2020, 1:30 p.m.

Panel Version: 2.172

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 32439617
• 32343227
• 32427099

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Seven unrelated individuals with a recurrent de novo variant reported; seizures are a consistent feature. This gene meets criteria for Green rating, mechanism remains to be elucidated.

Created: 25 Jan 2020, 9:50 a.m. | Last Modified: 25 Jan 2020, 9:50 a.m.

Panel Version: 2.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; epilepsy

Publications

• 31278393

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Not listed on OMIM in association with disease phenotype. D'Orsi et al, 2017 (29156220) - 61 adult patients with epilepsy and intellectual disability - had a 302kb del (VUS) encompassing TRPM3 and MIR204 (case 8) - inheritance unknown. Dyment et al, 2019 (31278393) - 8 probands with a DEE phenotype, comprising intellectual disability, epilepsy and hypotonia - 7/8 had electrographically confirmed epilepsy - seizure types include absence, generalised tonic-clonic, infantile and sub-clinical). De novo het variants. 7/8 had a recurrent missense change V837M (ACMG classification - pathogenic) and the other variant was P937Q (ACMG classification VUS). V837 occupies a crucial position in the S4-S5 linker, a conserved helix which interacts with the TRP domain during gating. In TRPM3 a H bond is predicted between V837 and R978 of the TRP domain. In TRPM7 the analagous bind is essential, and even conservative substitutions -R1115Q render the channel inactive.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

I don't know

HGMDPro only lists 'DM?' variants, and only one is associated with epilepsy (but was a CNV which involved a deletion of this gene and MIR204, PMID 29156220). No phenotype association given on OMIM.

Created: 23 Aug 2019, 10:21 a.m. | Last Modified: 23 Aug 2019, 10:21 a.m.

Panel Version: 1.256

Publications

• 29156220

I don't know

Excluding the individual harbouring a VUS, 7 individuals from PMID:31278393 (Dyment et al 2019) had the same de novo heterozygous variant in TRPM3 (p.Val837Met). This paper was considered when previously reviewed by GLHs. An Amber rating was chosen because public databases confirm that heterozygous loss-of-function variants of TRPM3 are observed in the general population (heterozygous gnomAD truncating variants occur in 18 of 25 canonical coding exons) and therefore the authors reasoned that simple haploinsufficiency was unlikely to be the mechanism of disease in their cohort. Therefore added 'for-review' tag, for reassesment at next GLH review.

Created: 26 May 2020, 4:18 p.m. | Last Modified: 26 May 2020, 4:18 p.m.

Panel Version: 2.63

Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.

Created: 9 Sep 2019, 9:41 a.m. | Last Modified: 9 Sep 2019, 9:41 a.m.

Panel Version: 1.306

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Comment on list classification: TRPM3 was added to the panel and rated Green by Konstantinos Varvagiannis based on PMID:31278393 (Dyment et al 2019). Although 8 probands were reported, 1 proband carries a VUS and an additional splice variant in DDB1. Therefore only variant is pathogenic, and this is missense, and de novo in all cases. The authors also note that heterozygous LOF variants in TRPM3 are observed in the general population. Not yet associated with a disorder in Gene2Phenotype or OMIM. Therefore have rated Amber and added 'watchlist' tag awaiting further cases or additional functional studies.

Created: 9 Jul 2019, 2:12 p.m. | Last Modified: 9 Jul 2019, 2:12 p.m.

Panel Version: 1.144

PMID:31278393. Dyment et al 2019 describe 8 probands with a phenotype comprising ID, epilepsy (7/8- not recorded in indiv 5) and hypotonia. The individuals all had de novo heterozygous variant in TRPM3. 7 probands were heterozygous for a recurrent variant in TRPM3: (NM_020952.4):c.2509G>A, p.Val837Met- The ACMG catergorization of this variant is pathogenic. 1 proband (Indiv 8) was heterozygous for p.(Pro937Gln). This was observed once in GnomAD and is categorized as a VUS in ACMG criteria. Individual 8 also had a heterozygous splice site deletion in DDB1. Functional studies were not performed.

Created: 9 Jul 2019, 2:08 p.m. | Last Modified: 9 Jul 2019, 2:08 p.m.

Panel Version: 1.143

Green List (high evidence)

Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
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TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
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As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature

Created: 6 Jul 2019, 3:36 p.m. | Last Modified: 6 Jul 2019, 5:07 p.m.

Panel Version: 1.128

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior

Publications

• doi.org/10.1038/s41431-019-0462-x

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments