Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
Br J Dermatol. 2009 Oct;161(4):884-9. doi: 10.1111/j.1365-2133.2009.09339.x. Epub 2009 Jun 11.
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.
This study investigated the genotype-phenotype association between detailed skin phenotype and FLG genotype data in a population-based cohort of children.
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.
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.
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.
角蛋白丝聚合蛋白基因（FLG）中的缺失突变会导致寻常型鱼鳞病，并与特应性皮炎相关。然而，FLG 单倍体不足的皮肤表现尚未明确界定。
本研究旨在调查基于人群的儿童队列中详细皮肤表型与 FLG 基因型数据之间的基因型-表型关联。
对 7-9 岁的儿童进行皮肤科医生检查。记录寻常型鱼鳞病、特应性皮炎和皮肤干燥的特征，并使用三项目严重程度评分（Three Item Severity score）对湿疹严重程度进行分级。对每个孩子进行六种最常见的 FLG 无义突变（R501X、2282del4、R2447X、S3247X、3702delG、3673delC）的基因分型。使用 Fisher 精确检验比较表型组中的基因型频率；使用逻辑回归分析估计 FLG 无义基因型的优势比和外显率，并进行置换检验以研究不同基因型组中的湿疹严重程度。
该队列中有 10 名儿童患有寻常型鱼鳞病，其中 5 名患有轻中度湿疹。在有两个突变的个体中，FLG 无义突变的外显率为 55.6%，在有一个突变的个体中为 16.3%，在野生型个体中为 14.2%。将与 FLG 无义突变相关的已知皮肤特征（鱼鳞病、毛发角化病、掌跖过度线性和屈侧湿疹）相加，在有两个 FLG 突变的儿童中，外显率为 100%，在有一个 FLG 突变的儿童中，外显率为 87.8%，在野生型个体中，外显率为 46.5%（P<0.0001，Fisher 精确检验）。FLG 无义突变与更严重的湿疹相关（P=0.0042），但严重程度评分仅相差 1-2 分。观察到三种不同的掌跖过度线性模式，这是首次报道。
当分析中包含所有相关的皮肤特征时，FLG 单倍体不足的外显率似乎很高。FLG 无义突变与更严重的湿疹相关，但在人群中，其效应大小较小。
