The following is a summary of “Genotype-Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity,” published in the June 2024 issue of Dermatology by Wen, et al.

Junctional epidermolysis bullosa (JEB) is a rare autosomal recessive genodermatosis characterized by diverse clinical manifestations. Current genotype-phenotype models are inadequate in predicting JEB subtypes and characteristics, particularly for splice site variants, constituting a significant proportion of disease-causing mutations in JEB. For a study, researchers sought to assess the genetic and clinical features of a cohort of individuals with JEB, exploring genotype-phenotype correlations through bioinformatic analyses and comparison with previously reported variants.

About 18 unique variants in genes LAMB3, LAMA3, LAMC2, or COL17A1 were identified in 17 individuals with JEB. The cohort comprised seven severe JEB cases, nine intermediate JEB cases, and one case of laryngo-onycho-cutaneous syndrome. Comprehensive phenotyping was conducted for all intermediate JEB cases, revealing significant inter-individual variability. Splice site variants were analyzed using SpliceAI, an advanced artificial intelligence tool, to predict the resulting transcripts. Predicted functional consequences included exon skipping and cryptic splice site activation, potentially explaining disease severity and correlating with laminin-332 immunofluorescence. RT-PCR was employed in one case to investigate the produced RNA transcripts.

Seven of the identified variants were novel, expanding the genomic landscape of JEB. Deep phenotyping highlighted considerable heterogeneity among individuals with intermediate JEB. Splice site variant analysis with SpliceAI provided insights into potential functional effects, aiding in understanding disease severity. RT-PCR analysis further elucidated the RNA transcripts resulting from splice site variants.

The study enhanced our understanding of JEB’s genomic and phenotypic spectrum. Artificial intelligence tools, such as SpliceAI, hold promise in predicting the functional consequences of splice site variants, guiding further laboratory investigations. Analysis of RNA transcripts will contribute to delineating genotype-phenotype correlations for novel variants in JEB.

Reference: sciencedirect.com/science/article/pii/S0022202X23032050