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Palmoplantar keratodermas v4.3 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from ICHTHYOSIS VULGARIS to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; hereditary palmoplantar keratoderma, MONDO:0019272
Palmoplantar keratodermas v4.2 FLG Arina Puzriakova Publications for gene: FLG were set to 16444271; 16815158; 17030239; 17291859
Palmoplantar keratodermas v4.1 FLG Arina Puzriakova Tag Q3_25_MOI tag was added to gene: FLG.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska changed review comment from: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.
PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).
Functional studies: Newborn Flg(-/-) 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).; to: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.

PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).

Functional studies: Newborn Flg(-/-) 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 Palmoplantar keratodermas.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: 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). Both monoallelic and biallelic variants in FLG may cause palmoplantar keratoderma - PPK is frequently seen in combination with ichthyosis (PMID:36308042 Clabbers et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; Changed publications to: 16444271, 16550169, 22409988, 36308042
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22409988, 36308042; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, hereditary palmoplantar keratoderma, MONDO:0019272; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Palmoplantar keratodermas v3.27 FLG2 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: FLG2.
Tag Q4_23_NHS_review was removed from gene: FLG2.
Palmoplantar keratodermas v3.27 FLG2 Achchuthan Shanmugasundram reviewed gene: FLG2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v3.26 FLG2 Achchuthan Shanmugasundram Source Expert Review Green was added to FLG2.
Source NHS GMS was added to FLG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: FLG2.
Tag Q4_23_NHS_review tag was added to gene: FLG2.
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Classified gene: FLG2 as Amber List (moderate evidence)
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Gene: flg2 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v3.12 FLG2 Arina Puzriakova Publications for gene: FLG2 were set to PubMed: 28884927; 29505760
Palmoplantar keratodermas v3.11 FLG2 Arina Puzriakova Phenotypes for gene: FLG2 were changed from peeling skin syndrome-6 (PSS6) (MIM 618084) to Peeling skin syndrome 6, OMIM: 618084
Palmoplantar keratodermas v3.2 FLG2 Tom Cullup gene: FLG2 was added
gene: FLG2 was added to Palmoplantar keratodermas. Sources: Expert list
Mode of inheritance for gene: FLG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLG2 were set to PubMed: 28884927; 29505760
Phenotypes for gene: FLG2 were set to peeling skin syndrome-6 (PSS6) (MIM 618084)
Penetrance for gene: FLG2 were set to unknown
Review for gene: FLG2 was set to GREEN
Added comment: Recommend all peeling skin syndrome genes should be on R165 & R166
Sources: Expert list
Palmoplantar keratodermas v0.10 FLG Catherine Snow Publications for gene: FLG were set to
Palmoplantar keratodermas v0.5 FLG Rebecca Foulger Source London North GLH was added to FLG.
Palmoplantar keratodermas v0.4 FLG Rebecca Foulger reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Palmoplantar keratodermas v0.3 FLG Rebecca Foulger gene: FLG was added
gene: FLG was added to Palmoplantar keratodermas. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FLG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FLG were set to ICHTHYOSIS VULGARIS