ClinGen Dosage Sensitivity Curation Page

FLG

  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16444271 Smith F et al, 2006 reported 7 families with ichthyosis vulgaris, including three Irish families, two Scottish families and one family of European American ancestry (figure 2). Two loss-of-functions variants R501X and 2282del4(leads to a premature termination codon 107 bp downstream) were identified and the inheritance pattern defined as semi-dominant inheritance pattern. "Heterozygotes were assigned a mild phenotype with 90% penetrance, and homozygotes or compound heterozygotes were assigned as a severe phenotype with 100% penetrance". Further immunohistochemistry using the skin biopsy material from an R501X homozygote patient showed that absence of conserved filaggrin repeat peptides and absence of keratohyalin granules. "Immunohistochemical analysis of an R501X/2282del4 compound heterozygote gave identical results (figure 4)".
27793761 Blunder S et al, 2017 provided a comprehensive functional study to proof that FLG loss-of-function mutations lead to alterations in epidermal eicosanoid metabolism which could serve as an autocrine trigger of inflammation and impaired late epidermal differentiation in atopic dermatitis (AD). Based on their functional study using nonlesional skin of patients with FLG wild-type AD (WT/WT), FLG-mutated AD (FLG/WT), IV (FLG/FLG), or FLG WT control skin, they proposed that " FLG loss-of-function mutations in AD lead to attenuated FLG expression, enhanced expression of inflammatory cytokines, and increased AA levels. AA triggers inflammation by upregulating IL1B and TARC (thymus activation regulated cytokine). Conversely, IL-1? and TNF? increase AA (arachidonic acid) concentrations in keratinocytes . Enhanced 12-LOX (lipoxygenase) metabolism potentially leads to an increased conversion of AA into 12-HETE (hydroxy-eicosatetraenoic acid) in FLG-mutated AD. As a result, increased levels of 12-HETE impair late epidermal differentiation. " (Figure 6)
27667308 McLean WH 2016 proposed a model for the correlation between filaggrin deficiency and eczema risk based on literature summary. "Filaggrin deficiency correlates with eczema risk. People carrying two FLG null mutations express zero filaggrin protein in their epidermis and have a massive odds ratio of > 150, meaning that essentially all of these individuals get eczema. Heterozygous carriers of a null mutation have about 50% of the normal amount of filaggrin in their skin and have a high risk (8 ? ) of developing eczema. Finally, even within the so?called normal population, there is a ? 10% variation in the amount of filaggrin produced (due to a subtle type of sequence variation). People expressing about 90% of the normal amount of filaggrin have a small but significant eczema risk. In contrast, people expressing more than the average amount of filaggrin in their epidermis (110%), show a 40% protection from eczema (odds ratio 0?6). Thus, there is a strong correlation between the degree of genetically determined filaggrin deficency and the likelihood of developing eczema." (Figure 2) . Homozygous transgenic mice model provided experimental evidence for this hypothesis (PMID: 19349982). Causative mutation in a natural filaggrin mutant mouse present as "flaky tail".

Haploinsufficiency phenotype comments:

Variation in FLG has been shown to be associated with susceptibility to atopic dermatitis (AD), allergy and asthma as well as ichthyosis vulgaris in the case of two mutations in trans. An informative review by Brown and McLean (2012) (PMID:22158554) describes Ichthyosis vulgaris as "the most common inherited disorder of keratinisation, with an estimated prevalence of between 1 in 80 and 1 in 250 English schoolchildren...it is an autosomal semidominant condition with incomplete penetrance and variable expressivity, such that disease severity can vary considerably even within affected families." Phenotype is due to impaired epidermal permeability/barrier function; Smith et al. 2006 show that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization (PMID: 16444271). Heterozygotes with loss of function mutations exhibit milder phenotype with decreased penetrance compared to those with homozygous or compound mutations, who are more likely to exhibit a more severe phenotype. Brown and McLean also report that "subsequent investigations of the role of FLG null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis and peanut allergy." Of note, FLG is known to have intragenic copy number variation; "common allelic variants showing 10, 11, or 12 nearly identical tandem repeats in exon 3, each ?972?bp in length" have been previously described, "each repeat at the DNA level encodes a complete copy of the 324 amino-acid filaggrin polypeptide, the functional protein product of the gene" (Brown et al. 2012, PMID: 22071473). Brown et al. (2012) show that "CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility." These authors show that the "odds ratio of disease was reduced by a factor of 0.88 (95% confidence interval 0.78-0.98, P=0.025) for each additional unit of copy number." BMC Med Genet. 2018 Jul 18;19(1):120 PMID: 30021537 A gross deletion encompassing the STS gene ranging from exon 1-10 and the FLG c.3321delA mutation were identified in a 31-year old male proband. The proband's another sister and his two nephews carried only FLG c.3321delA mutation. Patients carried both mutations presented more severe symptom, while those only carried FLG c.3321delA mutation showed slight or normal phenotype. J Eur Acad Dermatol Venereol. 2017 Jun;31(6):1038-1043 PMID: 28213896 Andersen YMF et al, 2017 indicated the prevalence of homozygous FLG mutations was significantly higher in the actinic keratosis (AK) (n = 4, 0.8%) in comparison with the control group (n = 18, 0.2%), whereas the prevalence of heterozygous FLG mutations was lower. In hospital registry data, patients with atopic dermatitis (AD) exhibited an increased risk of AK than did psoriasis controls (adjusted OR 1.46; [95% CI 1.12-1.90]), whereas no difference in risk was observed between patients with ichthyosis vulgaris (IV) and AD. Summary: Loss of function variants in FLG is associated with ichthyosis vulgaris (IV) and are an important predisposing factor for atopic dermatitis (AD). IV shows autosomal hemidominant (semidominant) inheritance, and patients with bi-allelic FLG mutations tend to have severe IV phenotypes. McLean WH, 2016 (PMID: 27667308) summarized the genotype an phenotype correlation between Filaggrin deficiency and eczema risk. "People carrying two FLG null mutations express zero filaggrin protein in their epidermis (bottom panel) and have a massive odds ratio of > 150, meaning that essentially all of these individuals get eczema. Heterozygous carriers of a null mutation have about 50% of the normal amount of filaggrin in their skin and have a high risk (8 ? ) of developing eczema. Finally, even within the so?called normal population, there is a ? 10% variation in the amount of filaggrin produced (due to a subtle type of sequence variation). People expressing about 90% of the normal amount of filaggrin have a small but significant eczema risk. In contrast, people expressing more than the average amount of filaggrin in their epidermis (110%), show a 40% protection from eczema (odds ratio 0?6)".

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

DGV Gold Standard record (NR frequency:0.88%): Alkan 2009 reported in 22 out of 22 samples carrying CNV gain for chr1:152274651..152297679 which includes the whole FLG gene. No similar whole gene duplications are observed in gnomAD SV as of January 2020. At this time, due to the frequency of the DGV Gold Standard variant being driven by a small number of samples, the committee felt that this was not enough evidence to definitively rule out a potential role for triplosensitivity for this gene. Of note: McLean WH, 2016 (PMID: 27667308) indicated that people expressing more than the average amount of filaggrin in their epidermis (110%), show a 40% protection from eczema (odds ratio 0?6).