ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function 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".

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.