The Genomic and Phenotypic Landscape of Ichthyosis

• DOI: 10.1001/jamadermatol.2021.4242
• Publication Date: 2021-12-01T18:04:00Z
• Authors: Qisi Sun; Nareh M. Burgren; Shayan Cheraghlou; Amy S. Paller; Margarita Larralde; Lionel Bercovitch; Jonathan Levinsohn; Ivy Ren; Rong Hua Hu; Jing Zhou; Theodore Zaki; Ryan Fan; Charlie Tian; Corey Saraceni; Carol J. Nelson-W...; Erin Loring; Brittany G. Craiglow; Leonard M. Milstone; Richard P. Lifton; Lynn M. Boyden; Keith A. Choate
• Keywords: Genotype-phenotype distinction

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