SINE Insertion in LAMA3 in Dogs With Junctional Epidermolysis Bullosa
TL;DR
The spectrum of pathogenic LAMA3 variants associated with canine JEB is expanded and 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 is highlighted.
Abstract
ABSTRACT 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.