title: Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children.
abstract: BACKGROUND
  Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined.
  
  
  OBJECTIVE
  This study investigated the genotype-phenotype association between detailed skin phenotype and FLG genotype data in a population-based cohort of children.
  
  
  METHODS
  Children (n = 792) aged 7-9 years were examined by a dermatologist. Features of ichthyosis vulgaris, atopic eczema and xerosis were recorded and eczema severity graded using the Three Item Severity score. Each child was genotyped for the six most prevalent FLG null mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC). Fisher's exact test was used to compare genotype frequencies in phenotype groups; logistic regression analysis was used to estimate odds ratios and penetrance of the FLG null genotype and a permutation test performed to investigate eczema severity in different genotype groups.
  
  
  RESULTS
  Ten children in this cohort had ichthyosis vulgaris, of whom five had mild-moderate eczema. The penetrance of FLG null mutations with respect to flexural eczema was 55.6% in individuals with two mutations, 16.3% in individuals with one mutation and 14.2% in wild-type individuals. Summating skin features known to be associated with FLG null mutations (ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) showed a penetrance of 100% in children with two FLG mutations, 87.8% in children with one FLG mutation and 46.5% in wild-type individuals (P < 0.0001, Fisher exact test). FLG null mutations were associated with more severe eczema (P = 0.0042) but the mean difference was only 1-2 points in severity score. Three distinct patterns of palmar hyperlinearity were observed and these are reported for the first time.
  
  
  CONCLUSIONS
  Filaggrin haploinsufficiency appears to be highly penetrant when all relevant skin features are included in the analysis. FLG null mutations are associated with more severe eczema, but the effect size is small in a population setting.
authors.affiliation: Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK. sara.brown@ncl.ac.uk
authors.forename: S J
authors.initials: SJ
authors.lastname: Brown
authors.forename: C L
authors.initials: CL
authors.lastname: Relton
authors.forename: H
authors.initials: H
authors.lastname: Liao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: A
authors.initials: A
authors.lastname: Sandilands
authors.forename: W H I
authors.initials: WH
authors.lastname: McLean
authors.forename: H J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: N J
authors.initials: NJ
authors.lastname: Reynolds
mesh_terms: D002648:Child; D003876:Dermatitis, Atopic / Q000235:genetics; D004485:Eczema / Q000235:genetics* / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D011446:Prospective Studies; D012720:Severity of Illness Index
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins
references.citation: J Invest Dermatol. 2009 Mar;129(3):543-52
references.pmid: 19209157
references.citation: J Allergy Clin Immunol. 2004 May;113(5):832-6
references.pmid: 15131563
references.citation: J Invest Dermatol. 2008 Jul;128(7):1669-75
references.pmid: 18239616
references.citation: J Invest Dermatol. 2009 Apr;129(4):1042-5
references.pmid: 18987673
references.citation: J Invest Dermatol. 2007 Jul;127(7):1667-72
references.pmid: 17301831
references.citation: Nat Rev Mol Cell Biol. 2005 Apr;6(4):328-40
references.pmid: 15803139
references.citation: Pharmacogenomics. 2008 Apr;9(4):399-413
references.pmid: 18384254
references.citation: Mol Cell Biol. 1993 Jan;13(1):613-25
references.pmid: 8417356
references.citation: J Invest Dermatol. 2007 Mar;127(3):564-7
references.pmid: 16990802
references.citation: Dermatol Ther. 2004;17 Suppl 1:43-8
references.pmid: 14728698
references.citation: J Invest Dermatol. 2008 Jun;128(6):1430-5
references.pmid: 18049447
references.citation: Br J Dermatol. 1985 Jun;112(6):679-85
references.pmid: 4005167
references.citation: Nat Genet. 2006 Apr;38(4):441-6
references.pmid: 16550169
references.citation: J Invest Dermatol. 2005 May;124(5):1071-4
references.pmid: 15854050
references.citation: J Allergy Clin Immunol. 2007 Jul;120(1):150-5
references.pmid: 17512043
references.citation: J Invest Dermatol. 2006 Aug;126(8):1770-5
references.pmid: 16810297
references.citation: J Cell Biol. 2007 Apr 9;177(1):173-82
references.pmid: 17403930
references.citation: Acta Derm Venereol. 1999 Sep;79(5):356-9
references.pmid: 10494710
references.citation: Acta Derm Venereol. 2007;87(6):499-505
references.pmid: 17989887
references.citation: J Invest Dermatol. 2008 Aug;128(8):2117-9
references.pmid: 18305568
references.citation: Nat Cell Biol. 2007 Jun;9(6):666-74
references.pmid: 17515931
references.citation: J Allergy Clin Immunol. 2008 May;121(5):1203-1209.e1
references.pmid: 18396323
references.citation: Nat Genet. 2006 Mar;38(3):337-42
references.pmid: 16444271
references.citation: Br Med J. 1966 Apr 16;1(5493):947-50
references.pmid: 20790920
references.citation: J Allergy Clin Immunol. 2008 Oct;122(4):689-693
references.pmid: 18774165
references.citation: Nat Genet. 2007 May;39(5):650-4
references.pmid: 17417636
references.citation: Exp Dermatol. 2005 Oct;14(10):719-26
references.pmid: 16176279
references.citation: Nat Genet. 2005 Jan;37(1):56-65
references.pmid: 15619623
references.citation: J Allergy Clin Immunol. 2008 Apr;121(4):872-7.e9
references.pmid: 18325573
references.citation: Br J Dermatol. 2007 Oct;157(4):645-8
references.pmid: 17714568
references.citation: Arch Dermatol Res. 2005 Dec;297(6):235-41
references.pmid: 16261374
references.citation: J Cell Biol. 2003 Nov 24;163(4):901-10
references.pmid: 14638864
references.citation: Hum Mol Genet. 2005 Jan 15;14(2):335-46
references.pmid: 15590704
references.citation: Curr Opin Allergy Clin Immunol. 2008 Oct;8(5):406-10
references.pmid: 18769192
references.citation: J Allergy Clin Immunol. 2008 Apr;121(4):940-46.e3
references.pmid: 18313126
references.citation: J Invest Dermatol. 2008 Jun;128(6):1591-4
references.pmid: 18094728
references.citation: J Allergy Clin Immunol. 2008 May;121(5):1294-5; author reply 1295-6
references.pmid: 18395783
references.citation: J Invest Dermatol. 2008 Jun;128(6):1436-41
references.pmid: 18200065