Editors' Corner: Unmasking deep intronic variants

In this edition of Gene's "Editor's Corner", we highlight the growing importance of deep intronic variants, which are increasingly recognised as pathogenic contributors to hereditary disorders that remain unsolved after whole-exome sequencing (WES). Recent studies using whole genome sequencing (WGS), which, in contrast to WES, captures most noncoding regions, have shown that splice variants outside intron-exon junctions account for approximately 7 % to 15 % of all molecular diagnoses and are typically missed by exome sequencing. The recently published Gene article by Wang et al., 2025 (Gene 962, 2025, 149574), on a novel deep intronic SLC12A1 variant in Bartter syndrome type 1 neatly illustrates this problem. The variant was missed by exome-based approaches but identified by WGS and shown to alter splicing using a minigene assay. The study not only resolved the molecular diagnosis but also expanded the spectrum of SLC12A1 disease-causing variants. The described workflow, WGS to find candidate deep intronic changes followed by functional splicing assays to prove its effect, has become a standard paradigm for uncovering disease-causing deep intronic variants.