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Early onset or syndromic epilepsy v2.491 TMX2 Sarah Leigh Tag for-review was removed from gene: TMX2.
Early onset or syndromic epilepsy v2.491 TMX2 Sarah Leigh commented on gene: TMX2
Early onset or syndromic epilepsy v2.490 TMX2 Sarah Leigh Source Expert Review Green was added to TMX2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.279 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, OMIM:618730; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, MONDO:0032887
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.181 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence (PMID:31735293). Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.68 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy
Early onset or syndromic epilepsy v2.67 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures
Early onset or syndromic epilepsy v2.66 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Early onset or syndromic epilepsy v2.0 TMX2 Zornitza Stark reviewed gene: TMX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31735293, 31586943; Phenotypes: Microcephaly, ID, brain malformations, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.475 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to GREEN
Added comment: This gene was reviewed for the intellectual disability panel. Epilepsy is part of the phenotype. Therefore green rating should be considered.

From the ID panel :
A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

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Created: 26 Nov 2019, 11:21 p.m. | Last Modified: 26 Nov 2019, 11:21 p.m.
Panel Version: 2.1122

[Previous review]

PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
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There is no associated phenotype in OMIM/G2P/SysID.
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Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Sources: Literature