Hereditary neuropathy or pain disorder

Gene: FIG4

Green List (high evidence)

Comment on mode of inheritance: There is some evidence for the association between FIG4 and dominant Amyotrophic lateral sclerosis. While multiple cases have been reported, there is no convincing segregation data, or functional evidence to support a dominant disease mechanism. Hence, the mode of inheritance should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal'. An expert_review tag was added to ensure GMS agreement on the strength of evidence.

Created: 6 Oct 2026, 4:07 p.m. | Last Modified: 6 Oct 2026, 4:07 p.m.

Panel Version: 8.37

FIG4 ALS-related reports:
PMID: 38695966 Ferreira et al., 2024
Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases.

PMID: 36090855 Yilihamu et al., 2022
Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS.

PMID: 35021275 Liu et al., 2021
Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4.
2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4.

PMID: 29464931 Bertolin et al., 2018 - biallelic ALS case
Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile.

PMID: 28051077 Osmanovic et al., 2017
German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES.
5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L).

FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).

2021 review by Ian Berry on the Neurodegenerative disorders, adult onset panel:
"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: 6 Oct 2026, 4 p.m. | Last Modified: 6 Oct 2026, 4:07 p.m.

Panel Version: 8.37

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Amyotrophic lateral sclerosis 11, OMIM:612577; amyotrophic lateral sclerosis type 11, MONDO:0012945

Publications

• 28051077
• 29464931
• 35021275
• 36090855
• 38695966

The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 10:16 a.m. | Last Modified: 1 Feb 2023, 10:16 a.m.

Panel Version: 2.18

Green List (high evidence)

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) and Yunis-Varon syndrome OMIM:216340 are biallelic, therefore the mode of inheritance should be - BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this gene on this panel.

Created: 17 Aug 2021, 11:48 a.m. | Last Modified: 17 Aug 2021, 11:48 a.m.

Panel Version: 1.48

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Multiple C5s in Bristol. Also well established from looking at HGMD. First paper PMID:17572665 - mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Multiple papers since and one particularly common variant p.I41T

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Charcot Marie Tooth disease, type 4J, 611228; Amyotrophic lateral sclerosis 11, 612577; Yunis Varon syndrome, 216340

Publications

• 17572665

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

I don't know

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)

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

Green List (high evidence)

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

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Is on the Charcot-Marie- Tooth disease type 1 / Intermediate CMT NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.

Created: 10 Jun 2016, 12:56 p.m.