Intellectual disabilityGene: TRPM3
8 unrelated individuals with de novo variants in this gene. Recurrent variant p.(Val837Met) identified in 7/8, which I think is compelling evidence of pathogenicity for this variant, LoF unlikely as mechanism. This is extremely unlikely to be a chance occurrence. I agree the 8th individual with a different variant does not necessarily have the same diagnosis.
Created: 1 Mar 2020, 9:51 a.m. | Last Modified: 1 Mar 2020, 9:51 a.m.
Panel Version: 3.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability; epilepsy
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, 2:15 p.m. | Last Modified: 9 Jul 2019, 2:15 p.m.
Panel Version: 2.940
PMID:31278393. Dyment et al 2019 describe 8 probands with a phenotype comprising ID, epilepsy (7/8) 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, 2:13 p.m. | Last Modified: 9 Jul 2019, 2:13 p.m.
Panel Version: 2.938
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.
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).
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].
Created: 6 Jul 2019, 3:34 p.m. | Last Modified: 6 Jul 2019, 5:07 p.m.
Panel Version: 2.938
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Variants in this GENE are reported as part of current diagnostic practice
Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Tag missense tag was added to gene: TRPM3. Tag watchlist tag was added to gene: TRPM3.
Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
gene: TRPM3 was added gene: TRPM3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior Penetrance for gene: TRPM3 were set to unknown Mode of pathogenicity for gene: TRPM3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TRPM3 was set to GREEN gene: TRPM3 was marked as current diagnostic