Hereditary neuropathy

Gene: SLC12A6

Removed the for-review tag as this is a 100,000 genomes project panel that does not need GMS approval for changes.

Created: 6 Oct 2022, 9:34 p.m. | Last Modified: 6 Oct 2022, 9:34 p.m.

Panel Version: 1.455

Comment on mode of inheritance: Changing the mode of inheritance as this is a 100K only panel.

Created: 6 Oct 2022, 9:33 p.m. | Last Modified: 6 Oct 2022, 9:33 p.m.

Panel Version: 1.455

Green List (high evidence)

For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.

Created: 13 Jul 2020, 3:14 p.m. | Last Modified: 13 Jul 2020, 3:15 p.m.

Panel Version: 1.371

Associated with Agenesis of the corpus callosum with peripheral neuropathy 218000 in OMIM and as confirmed Gen2Phen gene. At least 10 biallelic variants were reported in at least 10 unrelated cases. 9/10 of these variants was terminating (PMID 12368912, 16606917, 17893295). Three de novo heterozygous missense variants have been identified in four unrelated cases with a milder phenotype of early- onset progressive Charcot- Marie-tooth disease (CMT) with or without spasticity (intermediate CMT)(PMID 31439721, 27485015). The authors of PMID 31439721 suggest that "autosomal- dominant inheritance of SLC12A6 variants also needs to be considered in patients with early- onset neuropathies". Furthermore, it will be important to understand the functional differences between the variants, as PMID 27485015 reported variant - p.Thr991Ala, resulted in increased potassium influx in Xenopus oocytes (gain-of-function), while the other missense variants identified so far had a loss-of-function effect in varying degrees (PMID 31439721).

Created: 13 Jul 2020, 3:11 p.m. | Last Modified: 13 Jul 2020, 3:11 p.m.

Panel Version: 1.371

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Agenesis of the corpus callosum with peripheral neuropathy 218000

Publications

• 12368912
• 16606917
• 17893295

Green List (high evidence)

2 unrelated patients with reported variants in Bristol. In one family two affected sibs were both found to be compound heterozygous. PMID: 12368912 - reported mice with a targeted deletion of the Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a sensorimotor gating deficit, similar to the human disease

Created: 29 Apr 2019, 12:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Publications

• 12368912

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

Green List (high evidence)

The Neurology Specialist Test Group agreed that this gene was recommended for the WGS panel based on a broader phenotype view to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. This panel includes conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation. This panel as going to be used for R78, 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 and as a result a new panel was created https://panelapp.genomicsengland.co.uk/panels/846/ for this purpose.

Created: 7 Dec 2019, 6:08 p.m. | Last Modified: 7 Dec 2019, 6:08 p.m.

Panel Version: 1.352

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Review and rating submitted by Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.

Created: 29 Apr 2019, 12:53 p.m.

Green List (high evidence)

Green List (high evidence)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Complex phenotype, notpure CMT

Created: 9 Dec 2015, 8:49 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Complex phenotype, notpure CMT

Created: 8 Dec 2015, 3:05 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal