Hereditary neuropathy or pain disorder

Gene: SLC25A46

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 10 Oct 2023, 6:06 p.m. | Last Modified: 10 Oct 2023, 6:06 p.m.

Panel Version: 3.58

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in neuropathy, hereditary motor and sensory, type VIB (MIM# 616505), as identified from biallelic loss-of-function variants from at least 5 unrelated individuals/ families from multiple ethnicities and supported by results from animal models.

Seven patients from three un-related families of various ethnicities carrying either homozygous or compound heterozygous variants (c.165_166insC/ p.His56fs*94 & c.746G>A/ p.Gly249Asp, c.1018C>T/ p.Arg340Cys and c.1005A>T/ p.Glu335Asp) were reported with optic atrophy and peripheral neuropathy that manifest as axonal Charcot-Marie-Tooth disease (MIM# 616505). However, there was phenotypic variability in age at onset, additional clinical features, and severity (PMID:26168012).

Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes (PMID:27430653).

A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502).

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in both OMIM and Gene2Phenotype.

Created: 11 Dec 2022, 10:24 a.m. | Last Modified: 11 Dec 2022, 10:24 a.m.

Panel Version: 2.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neuropathy, hereditary motor and sensory, type VIB, OMIM:616505; Pontocerebellar hypoplasia, type 1E, OMIM:619303, MONDO:0030260

Publications

• 26168012
• 27430653
• 28376086
• 28934388
• 30178502

I don't know

Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - syndrome with non-neurological features / Broader phenotype: Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy

Created: 7 Dec 2019, 12:03 a.m. | Last Modified: 7 Dec 2019, 12:03 a.m.

Panel Version: 0.86

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 10:25 p.m. | Last Modified: 6 Dec 2019, 10:25 p.m.

Panel Version: 0.84

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy

Publications

• 26168012