The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.-猫眼课题宝

DOI：

10.1001/jamadermatol.2021.4242

发表时间：

2021-12

期刊：

JAMA dermatology

影响因子：

10.9

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Qisi Sun;N. M. Burgren;S. Cheraghlou;A. Paller;M. Larralde;L. Bercovitch;J. Levinsohn;Ivy Ren;R. Hu;Jing Zhou;T. Zaki;R. Fan;C. Tian;Corey Saraceni;C. Nelson-Williams;E. Loring;B. Craiglow;L. Milstone;R. Lifton;L. Boyden;K. Choate

鱼鳞病是一种临床和遗传异质性疾病，以鳞状皮肤为特征。尽管几十年来的研究已经确定了50多个基因的致病变异，但很难建立明确的基因型-表型关联。目的扩大鱼鳞病的基因型和表型谱，探讨基因型与表型的关系。该队列研究招募了一组国际鱼鳞病患者，并描述了从2011年6月到2021年7月的10年期间常见基因型的特征和显著特征，包括基因型-表型关联。所有年龄、种族和民族的参与者被纳入，并从世界各地的转诊中心和患者倡导团体登记入组。基因诊断的患者完成了一份评估临床表现的问卷。唾液或血液DNA的遗传分析，表型调查问卷和标准化临床照片。描述性统计，如频率计数，用于描述队列中的病例。Fisher精确测试确定了显著的基因型-表型关联。结果报告了来自世界各地的1000名无血缘关系个体的结果（平均[SD]年龄50.0[34.0]岁，524[52.4%]名女性，427[42.7%]名男性，49[4.9%]名未分类）；75%来自美国，12%来自拉丁美洲，4%来自加拿大，3%来自欧洲，3%来自亚洲，2%来自非洲，1%来自中东，1%来自澳大利亚和新西兰。在869个种属中，共鉴定出32个基因的266个新的疾病相关变异。其中，通过多重扩增子测序发现241个（91%）致病变异，通过外显子组测序发现25个（9%）致病变异。在869名有基因诊断的参与者中，304名参与者（35%）完成了表型问卷。对这304名患者的临床表现分析显示，瘙痒、缺水、皮肤疼痛、眼部问题、皮肤气味和皮肤感染是最普遍的自我报告特征。基因型-表型关联分析显示，与所研究的其他鱼鳞病基因型相比，出生时存在胶膜（比值比[OR]， 6.7; 95% CI, 3.0-16.7; P < 0.001）、皮肤气味（比值比[OR]， 2.8; 95% CI, 1.1-6.8; P = 0.02）、听力问题（比值比，2.9;95% CI, 1.6-5.5; P < 0.001）、眼病（比值比，3.0;95% CI, 1.5-6.0; P < 0.001）和脱发（比值比，4.6;95% CI, 2.4-9.0; P < 0.001）与TGM1变异显著相关。皮肤疼痛（OR, 6.8; 95% CI, 1.6-61.2; P = 0.002）、气味（OR, 5.7; 95% CI, 2.0-19.7; P < 0.001）和感染（OR, 3.1; 95% CI, 1.4-7.7; P = 0.03）与引起鱼鳞病的其他基因的疾病相关变异相比，与KRT10致病变异显著相关。在869名（86.9%）参与者中鉴定出致病变异。大多数剩下的个体都有独特的表型，这使得进一步的遗传发现成为可能。结论和相关性本队列研究扩展了鱼鳞病的基因型和表型谱，建立了临床表现与基因型之间的联系。总的来说，这些发现可能有助于改善临床评估，协助制定定制的管理计划，并改善临床病程预测。

Importance Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish. Objective To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations. Design, Setting, and Participants This cohort study recruited an international group of individuals with ichthyosis and describes characteristic and distinguishing features of common genotypes, including genotype-phenotype associations, during a 10-year period from June 2011 to July 2021. Participants of all ages, races, and ethnicities were included and were enrolled worldwide from referral centers and patient advocacy groups. A questionnaire to assess clinical manifestations was completed by those with a genetic diagnosis. Main Outcomes and Measures Genetic analysis of saliva or blood DNA, a phenotyping questionnaire, and standardized clinical photographs. Descriptive statistics, such as frequency counts, were used to describe the cases in the cohort. Fisher exact tests identified significant genotype-phenotype associations. Results Results were reported for 1000 unrelated individuals enrolled from around the world (mean [SD] age, 50.0 [34.0] years; 524 [52.4%] were female, 427 [42.7%] were male, and 49 [4.9%] were not classified); 75% were from the US, 12% from Latin America, 4% from Canada, 3% from Europe, 3% from Asia, 2% from Africa, 1% from the Middle East, and 1% from Australia and New Zealand. A total of 266 novel disease-associated variants in 32 genes were identified among 869 kindreds. Of these, 241 (91%) pathogenic variants were found through multiplex amplicon sequencing and 25 (9%) through exome sequencing. Among the 869 participants with a genetic diagnosis, 304 participants (35%) completed the phenotyping questionnaire. Analysis of clinical manifestations in these 304 individuals revealed that pruritus, hypohydrosis, skin pain, eye problems, skin odor, and skin infections were the most prevalent self-reported features. Genotype-phenotype association analysis revealed that the presence of a collodion membrane at birth (odds ratio [OR], 6.7; 95% CI, 3.0-16.7; P < .001), skin odor (OR, 2.8; 95% CI, 1.1-6.8; P = .02), hearing problems (OR, 2.9; 95% CI, 1.6-5.5; P < .001), eye problems (OR, 3.0; 95% CI, 1.5-6.0; P < .001), and alopecia (OR, 4.6; 95% CI, 2.4-9.0; P < .001) were significantly associated with TGM1 variants compared with other ichthyosis genotypes studied. Skin pain (OR, 6.8; 95% CI, 1.6-61.2; P = .002), odor (OR, 5.7; 95% CI, 2.0-19.7; P < .001), and infections (OR, 3.1; 95% CI, 1.4-7.7; P = .03) were significantly associated with KRT10 pathogenic variants compared with disease-associated variants in other genes that cause ichthyosis. Pathogenic variants were identified in 869 (86.9%) participants. Most of the remaining individuals had unique phenotypes, enabling further genetic discovery. Conclusions and Relevance This cohort study expands the genotypic and phenotypic spectrum of ichthyosis, establishing associations between clinical manifestations and genotypes. Collectively, the findings may help improve clinical assessment, assist with developing customized management plans, and improve clinical course prognostication.

The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.

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