Ichthyosis and erythrokeratoderma

Gene: FLG

Green List (high evidence)

Comment on list classification: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.

Created: 18 Sep 2025, 4:23 p.m. | Last Modified: 18 Sep 2025, 4:23 p.m.

Panel Version: 4.1

There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.

Created: 18 Sep 2025, 4:20 p.m. | Last Modified: 18 Sep 2025, 4:25 p.m.

Panel Version: 4.1

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' at the next update.

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, 12:04 p.m. | Last Modified: 18 Sep 2025, 12:04 p.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
• 24940654
• 22409988
• 33807935
• 36716921
• 36751330

I don't know

Comment on list classification: Sufficient evidence and phenotype to be relevant as Green in the panel

Created: 12 Dec 2019, 2:50 p.m. | Last Modified: 12 Dec 2019, 2:50 p.m.

Panel Version: 0.11

This gene was part of a gene list collated by John McGrath, KCL and Veronica Kinsler, UCL, 17.Jun.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?): none provided.

Created: 9 Sep 2019, 3:38 p.m. | Last Modified: 9 Sep 2019, 3:38 p.m.

Panel Version: 0.10