Genotype-phenotype study of 149 epidermolysis bullosa simplex patients in North America

Summary: Abstract Body: Background: Epidermolysis Bullosa Simplex (EBS) is the most common type of EB, with varying severity, from localized blistering on extremities to widespread skin and mucosal wounds. Method: Prospective cohort study of 152 genetically confirmed EBS patients from the Epidermolysis Bullosa Clinical Research Consortium (EBCRC). Results: The mean age of subjects was 11.2 years, 51% were <10 years old. Mean age at diagnosis was 19 days and 55% had a family history. There was an equal number of males: females, 73% were White (12% Hispanic), 9% Black, 4% Asians, 2% Middle Eastern, and 1% American Indian. The most common clinical subtypes were generalized severe or intermediate (22%), localized (20%), and EBS with muscular dystrophy (5%). Most pathogenic variants occurred in KRT5 (28%) and KRT14 (29%), followed by PLEC (15%). 80% were missense, 5% nonsense, and 10% frameshift. Nonsense variants were found in 12% of generalized cases but none in localized EBS (P=0.05). Keratin intermediate filaments consist of 3 domains: a central α-helical "rod" domain flanked by head and tail domains. Almost all KRT14 variants occurred in the α-helical domain (97%), in contrast to KRT5 variants (49%, P=0.001). We found common hotspots (KRT14 p.R125C and p.R125H), but also novel pathogenic variants (KRT14 p.A127P and p.E411G). Nonsense variants frequently lead to severe clinical manifestations; however, for missense variants, the location of the variant plays a more critical role than the specific amino acid change in KRT5 or KRT14. Ongoing genotype-phenotype analyses will enhance our understanding of the underlying genetic mechanisms and may aid in disease prognosis. To our knowledge, this is the largest genotype-phenotype study in a diverse population from North America. Yuri Ikeda¹, Estephannie Alvarez¹, Anne W. Lucky², Emily Gorell², Kathleen G. Peoples³, Joyce Teng¹, Anna L. Brucker³, Jean Y. Tang^{1, 4} 1. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States. 2. Division of Dermatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. 3. Dermatology, Children's Hospital Colorado, Aurora, CO, United States. 4. presenting for EBCRC investigators, Stanford, CA, United States. Clinical Research: Epidemiology and Observational Research