A junction-level skip index for NR5A1 distinguishes adrenocortical carcinoma from normal adrenal

Abstract Steroidogenic factor 1 (SF-1, NR5A1 ) sets the transcriptional capacity of the adrenal cortex. Its pre-mRNA can be spliced so that an upstream exon joins directly to exon 7, removing two or more internal exons and abolishing the full-length receptor. We asked how often this happens in human tissue, using public RNA-seq rather than new material. We defined a skip index as the summed coverage of the exon 2→7, exon 3→7 and exon 4→7 junctions divided by the coverage of the exon 6→7 junction, computed per sample from Snaptron junction counts. Among NR5A1 -expressing tissues in GTEx, the index was highest in ovary (median 4.27%, n = 180) and lowest in adrenal gland (0.38%, n = 270), which carried the largest denominator of any tissue examined. Most of the elevation in testis was accounted for by a genome-wide splicing background six times that of adrenal: normalised to that background, testis stood 1.3-fold above adrenal, against 7.0-fold for ovary. In TCGA-ACC the index was 0.90% (n = 73), higher than normal adrenal (p = 5.3 × 10⁻⁵; background-normalised p = 1.1 × 10⁻⁶), and was not explained by read depth, splicing background or tumour purity. Within tumours it correlated inversely with steroidogenic gene expression (rho = − 0.33, p = 0.004) but not with Weiss grade (rho = 0.14, p = 0.30).