Adult onset neurodegenerative disorder
Gene: ITM2B
two families reported - large British family with 12 affected in 3 generations; spasticity onset age 40-60 and progressive mental deterioration. No male to male transmission noted. Stop codon variant. Second Danish family, with 9 affected in 5 generations. Also no male to male transmission; cataracts before age 30 followed by cerebellar ataxia then dementia - fs that also leads to extended protein. No other variants with similar disease mechanism are reported in HMGDpro - only missense with limited evidence for pathogenicity other than in silico predictions. 2 cases - Amber?Created: 2 Sep 2019, 4:06 p.m. | Last Modified: 2 Sep 2019, 4:06 p.m.
Panel Version: 1.99
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Dementia, familial British, 176500
Publications
Mode of pathogenicity
Other - please provide details in the comments
Few mutations reported.Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.
Panel Version: 1.72
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Dementia, familial British, 176500
Publications
Variants in this GENE are reported as part of current diagnostic practice
Prior to GLH sign off for this panel, ITM2B was discussed further by the specialist test group. It was agreed by all GLHs (Wessex and West Midlands GLH, Yorkshire and North East GLH, London North GLH) to keep this gene Green.
It was highlighted that two fs variants and one missense rated red on HGMDpro - missense likely pathogenic using in silico tools only. Second amber rated missense in association with dementia. Only 2 cases with segregation - so it was suggested the gene should be Amber not Green. However, further feedback confirmed the Green rating as it was noted that this is rare, but there are a couple of families with a stop-loss mutation in this gene reported in one of the labs, so should remain green.Created: 28 Nov 2019, 2:01 p.m. | Last Modified: 28 Nov 2019, 2:01 p.m.
Panel Version: 1.115
As discussed with the GMS Neurology Specialist Test Group webex call11th September 2019 : The Specialist Test Group all agreed that there is enough evidence to rate this gene GreenCreated: 20 Sep 2019, 4:19 p.m. | Last Modified: 20 Sep 2019, 4:19 p.m.
Panel Version: 1.106
Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.Created: 2 Sep 2019, 4:46 p.m. | Last Modified: 2 Sep 2019, 4:46 p.m.
Panel Version: 1.101
Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.
Panel Version: 1.74
Review and rating submitted byJames Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.Created: 23 Apr 2019, 5:35 p.m.
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: ITM2B were changed from Dementia, familial British, OMIM:176500 to Dementia, familial British, OMIM:176500; ABri amyloidosis, MONDO:0008306; Dementia, familial Danish, OMIM:117300; ADan amyloidosis, MONDO:0007297
Publications for gene: ITM2B were set to 29525180; 10391242; 10781099
Publications for gene: ITM2B were set to 29525180; 10391242; 210391242; 10781099
Phenotypes for gene: ITM2B were changed from Dementia, familial British, 176500 to Dementia, familial British, OMIM:176500
Publications for gene: ITM2B were set to 29525180; 10391242
Source Wessex and West Midlands GLH was added to ITM2B.
Publications for gene ITM2B were changed from to 29525180; 10391242
Source Yorkshire and North East GLH was added to ITM2B.
Source NHS GMS was added to ITM2B.
Source London North GLH was added to ITM2B.
Louise Daugherty: Comment on phenotypes: amended
gene: ITM2B was added gene: ITM2B was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: ITM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ITM2B were set to Dementia, familial British, 176500