BG08: JEBseq: a novel database to explore genotype–phenotype correlation in junctional epidermolysis bullosa

Extract

D. Wen,^1,2 D. Balacco,³ A. Bardhan,^1,2 N. Harper,² M. Ogboli,⁴ L. Ozoemena,⁵ L. Liu,⁵ I. Chapple^1,3,6 and A. Heagerty^1,2

¹Dermatology Research Group and ³School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; ²Adult Epidermolysis Bullosa Unit, Department of Dermatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; ⁴Paediatric Epidermolysis Bullosa Unit, Department of Paediatric Dermatology, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK; ⁵National Diagnostic EB Laboratory, Viapath, St Thomas’ Hospital, London, UK; ⁶Birmingham Dental Hospital, Birmingham Community Health NHS Foundation Trust, Birmingham, UK

Junctional epidermolysis bullosa (JEB) is an autosomal recessive genodermatosis characterized by skin cleavage within the lamina lucida arising as a result of abnormalities in structural proteins of the dermoepidermal junction. Genes implicated in severe JEB, intermediate JEB and laryngo‐onychocutaneous (LOC) syndrome include LAMA3, LAMB3, LAMC2 and COL17A1 (Bardhan A, Bruckner‐Tuderman L, Chapple ILC et al. Epidermolysis bullosa. Nat Rev Dis Primers 2020; 6: 78). Classical genotype–phenotype correlation approaches suggest that biallelic null mutations in LAMA3, LAMB3 or LAMC2 result in severe JEB with mortality within 24 months of life (Has C, Bauer JW, Bodemer C et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Br J Dermatol 2020; 183: 614–27). Intermediate phenotypes typically result from mono‐ or biallelic variants allowing residual protein expression in these three genes, or biallelic mutations in COL17A1 (Has et al.). This study aims to collect, annotate and characterize mutations associated with JEB through bioinformatic approaches. Mutations, along with detailed phenotypes, will be stored in a novel open‐access database, JEBseq, to explore genotype–phenotype correlations. Nineteen mutations were identified in 16 affected individuals (13 homozygotes and three compound heterozygotes) who attended a highly specialized EB service from 2015 to 2020. Genotyping was performed by the national diagnostic EB laboratory, and mutations were confirmed through polymerase chain reaction and bidirectional sequencing. Three indel mutations causing frameshifts and premature termination codons (PTCs) were found in LAMA3 and two in LAMC2. Mutations in LAMB3 included five nonsense mutations, four splice‐site mutations and an out‐of‐frame deletion. Mutations in COL17A1 included one insertion resulting in a frameshift and PTC, one splice‐site mutation and two large deletions (both approximately 3 kilo base pairs). Six of these variants are currently unreported in extant databases (ClinVar, Ensembl). Observed phenotypes included severe JEB (seven individuals), intermediate JEB (eight individuals) and LOC syndrome (one individual). Most phenotypes are consistent with existing genotype–phenotype paradigms, with all COL17A1 mutations resulting in intermediate JEB. However, two patients presented homozygous nonsense or frameshift mutations in LAMB3, and one patient was a compound heterozygote for a nonsense and splice‐site variant in LAMB3, yet these three individuals displayed intermediate phenotypes and survived beyond early childhood. This study identifies novel variants in JEB and highlights that phenotypes may be milder than existing genotype–phenotype paradigms suggest. There is a need for a more detailed understanding of genotype–phenotype correlations to inform stratified clinical care and, owing to the rarity of JEB, collection of variants into a specific database will be essential for this. JEBseq aims to act as a central open‐access database whereby comprehensive deep phenotyping can be correlated with genetic data and complementary in silico analyses exploring transcript splicing, stability and protein structure and function.