Rare genetic inflammatory skin disorders

Gene: FLG

Red List (low evidence)

Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

Created: 18 Sep 2025, 9:27 a.m. | Last Modified: 18 Sep 2025, 9:27 a.m.

Panel Version: 4.1

Comment on list classification: As reviewed by Ronnie Wright, FLG is associated with Ichthyosis vulgaris, which does not fit into the current scope of the Rare genetic inflammatory skin disorders panel. It should be rated Red based on the available evidence.

The gene is already rated Green on the following panels: Ichthyosis and erythrokeratoderma and Palmoplantar keratodermas.

FLG is associated with Ichthyosis vulgaris (AD &AR) OMIM:146700 and {Dermatitis, atopic, susceptibility to, 2} AD OMIM: 605803 in OMIM (accessed 18th Sep 2025).

Created: 18 Sep 2025, 9:19 a.m. | Last Modified: 18 Sep 2025, 9:19 a.m.

Panel Version: 4.1

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM: 605803; ichthyosis vulgaris, MONDO:0024304

Publications

• 16444271
• 16550169

Green List (high evidence)

Gene is associated with Ichthyosis vulgaris. LOF variants are disease causing

Evidence indicates a semi-dominant inheritance pattern where biallelic LOF variants cause severe Ichthyosis vulgaris. Heterozygous LOF variants are associated with increased eczema risk, with reduced penetrance.

Created: 27 Jun 2025, 9:16 a.m. | Last Modified: 27 Jun 2025, 9:16 a.m.

Panel Version: 4.1

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Publications

• PMID:16444271

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

I don't know

Evidence for common FLG pathogenic variants associated with atopic dermatitis, but phenotype is not covered by testing criteria document.

Created: 12 Dec 2019, 3:08 p.m. | Last Modified: 12 Dec 2019, 3:08 p.m.

Panel Version: 0.21

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Ichthyosis vulgaris; Eczema; Ichthyosis vulgaris 146700

Publications

• 16550169

Comment on publications: PMID: 17291859 - report a truncating variant and indel identified in Japanese patients with ichthyosis vulgaris and atopic dermatitis.

Created: 1 Mar 2019, 10:28 a.m.

Comment on publications: PMID: 16815158 and 17030239 are susceptibility studies that have shown an association of two loss-of-function variants in this gene, and susceptibility to extrinsic atopic dermatitis, allergic sensitization, total IgE level, asthma, and palmar hyperlinearity, eczema.

Created: 1 Mar 2019, 10:06 a.m.

Comment on publications: PMID: 16444271 - reports 7 unrelated families and 8 sporadic cases with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon (rs61816761), or compound heterozygous for this variant and a frameshift variant (rs558269137). Homozygous/compound heterozygous cases had more pronounced phenotype.

Created: 1 Mar 2019, 10:02 a.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

This gene was part of an initial gene list collated by Thomas Cullup, GOSH and Veronica Kinsler, UCL, 25.Jan.2019 on behalf of the GMS Skin Specialist Test Group. Gene Symbol submitted: FLG; Suggested initial gene rating: Green; Evidence for inclusion: none provided; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): Hard to sequence with short-read sequencing (highly repetitive)

Created: 31 Jan 2019, 2:02 p.m.

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