SINE Insertion in LAMA3 in Dogs With Junctional Epidermolysis Bullosa

Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder caused by defects in proteins responsible for dermal-epidermal adhesion. We investigated the genetic cause of JEB in three related mixed-breed puppies presenting with congenital skin blistering and ulceration. Whole-genome sequencing of one affected dog followed by comparison with 1538 control genomes identified a private candidate variant, XM_038543644.1:c.5690_5691ins240, in LAMA3, a known JEB-associated gene. Visual inspection of the short-read alignments and Sanger sequencing revealed a homozygous 240-bp SINE insertion in exon 45 that had initially been miscalled as a heterozygous short insertion. Fragment length analysis confirmed complete co-segregation of the variant with the disease phenotype within the available family. The SINE insertion is flanked by a 16-bp target site duplication, contains a 45-nt poly(A) tail, and is predicted to remain in-frame, introducing an additional 80 amino acids into the laminin α3 coiled-coil domain without introducing a premature stop codon. Although the molecular consequences were not functionally investigated, the insertion is expected to disrupt normal laminin-332 heterotrimer assembly and secretion. This study expands the spectrum of pathogenic LAMA3 variants associated with canine JEB and highlights the importance of visual inspection of short-read sequencing data for the detection and correct interpretation of structurally complex variants such as transposable element insertions.