Adult onset neurodegenerative disorder
Gene: FIG4The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 12:22 p.m. | Last Modified: 1 Feb 2023, 12:22 p.m.
Panel Version: 3.49
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 10 Mar 2022, 4:12 p.m. | Last Modified: 10 Mar 2022, 4:12 p.m.
Panel Version: 2.263
Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, in response to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816, which shows a lack of evidence for ALS.
Created: 28 Oct 2021, 12:13 p.m. | Last Modified: 28 Oct 2021, 12:20 p.m.
Panel Version: 2.201
The Q3_21_MOI tag has been added as Amyotrophic lateral sclerosis 11 (OMIM:612577) is monoallelic and Charcot-Marie-Tooth disease, type 4J (OMIM:611228) is biallelic, therefore the mode of inheritance should be - BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this gene on this panel.Created: 13 Aug 2021, 9:24 a.m. | Last Modified: 17 Aug 2021, 10:19 a.m.
Panel Version: 2.187
Associated with relevant phenotype in OMIM, but not associated with Amyotrophic lateral sclerosis 11 (OMIM:612577) or Charcot-Marie-Tooth disease, type 4J (OMIM:611228) in Gen2Phen. At least three variants reported in three cases of Amyotrophic lateral sclerosis 11 (OMIM:612577)(PMID: 19118816), and two variants in at least one case of Charcot-Marie-Tooth disease, type 4J (OMIM:611228)(PMID: 21705420).Created: 13 Aug 2021, 9:22 a.m. | Last Modified: 13 Aug 2021, 9:22 a.m.
Panel Version: 2.182
Comment on phenotypes: Amyotrophic lateral sclerosis 11 OMIM:612577 is associated with this panel (Neurodegenerative disorders - adult onset) as it is an adult onset condition. Charcot-Marie-Tooth disease, type 4J, 611228 is predominantly a childhood condition, however, some adult cases have been reported (PMID: 21705420).Created: 13 Aug 2021, 9:06 a.m. | Last Modified: 13 Aug 2021, 9:06 a.m.
Panel Version: 2.182
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Association of FIG4 with ALS remains in question. Main evidence is from Chow 2009 paper PMID: 19118816 where 5 proven deleterious variants were identified in a 473 patient cohort. There are 666 rare (<5 instances) protein altering & splice donor/acceptor variants in gnomAD v.2.1 https://gnomad.broadinstitute.org/gene/ENSG00000112367?dataset=gnomad_r2_1, with a denominator of ~125,000 patients. Other studies of FIG4 in ALS cohorts are under-powered to show a clear enrichment of proven deleterious alleles.
Using Pearson's Chi-squared test these two cohorts do not have a significant difference in rare/deleterious variant rate at p.<0.05.
I haven't seen any convincing segregation evidence for a FIG4 variant in a large ALS family, and am unaware of any functional studies or animal models showing a convincing genotype-phenotype association. I do not think this gene (yet) clearly satisfies the threshold of probability for a dominant cause of ALS.Created: 14 May 2021, 10:19 a.m. | Last Modified: 14 May 2021, 10:19 a.m.
Panel Version: 2.174
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Chow et al. (2009) reported 5 unrelated patients diagnosed with probable or definite ALS. Two had a family history of the disorder. All had adult onset and showed prominent corticospinal tract findings. Nerve conduction velocity studies were normal, but EMG studies showed some denervation. Autosomal recessive Charcot-Marie Tooth disease type 4J (CMT4J; 611228) is an allelic disorder with a much more severe phenotype.GreenCreated: 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, imprinted status unknown
Phenotypes
Charcot-Marie-Tooth disease, type 4J, 611228; Amyotrophic Lateral Sclerosis, Dominant
Late onset 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, imprinted status unknown
Phenotypes
Charcot-Marie-Tooth disease, type 4J, 611228; Amyotrophic Lateral Sclerosis, Dominant
Publications
Variants in this GENE are reported as part of current diagnostic practice
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
Tag Q3_21_MOI was removed from gene: FIG4.
Mode of inheritance for gene FIG4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tag Q3_21_NHS_review was removed from gene: FIG4. Tag Q4_21_expert_review was removed from gene: FIG4.
Source Expert Review Red was added to FIG4. Rating Changed from Green List (high evidence) to Red List (low evidence)
Tag Q4_21_expert_review tag was added to gene: FIG4.
Tag Q3_21_NHS_review tag was added to gene: FIG4.
Tag Q3_21_MOI tag was added to gene: FIG4.
Phenotypes for gene: FIG4 were changed from Amyotrophic lateral sclerosis 11, OMIM:612577; amyotrophic lateral sclerosis type 11 MONDO:0012945; Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640 to Amyotrophic lateral sclerosis 11 OMIM:612577; amyotrophic lateral sclerosis type 11 MONDO:0012945; Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640
Publications for gene: FIG4 were set to 19118816; 23888880
Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Amyotrophic lateral sclerosis 11, OMIM:612577 to Amyotrophic lateral sclerosis 11, OMIM:612577; amyotrophic lateral sclerosis type 11 MONDO:0012945; Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640
Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J, 611228; Amyotrophic Lateral Sclerosis, Dominant to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Amyotrophic lateral sclerosis 11, OMIM:612577
Source Wessex and West Midlands GLH was added to FIG4.
Publications for gene FIG4 were changed from PMID: 19118816 to 19118816; 23888880
Source Yorkshire and North East GLH was added to FIG4.
Source NHS GMS was added to FIG4.
Source London North GLH was added to FIG4.
Louise Daugherty: Comment on phenotypes: amended
gene: FIG4 was added gene: FIG4 was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: FIG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FIG4 were set to PMID: 19118816 Phenotypes for gene: FIG4 were set to Charcot-Marie-Tooth disease, type 4J, 611228; Amyotrophic Lateral Sclerosis, Dominant