Hypomorphic alleles pose challenges in rare disease genomic variant interpretation

Abstract

Exon skipping associated with an ATP7B intronic variant in a patient with Wilson's disease. (A) Sashimi plot visualization of aligned RNA sequencing data from proband liver tissue at ATP7B exons 14-13-12. The red track shows traditional RNA-seq data; the blue track shows RNA-seq enriched with exon capture (cDNA-cap) which achieves higher depth of protein-coding transcripts. The histogram indicates overall sequencing depth while arcs tabulate the number of junction-spanning reads supporting exon pairs. (B) The domain structure (top) and exon structure (bottom) of ATP7B. Loss of exon 13 (dashed box) would remove a transmembrane domain and disrupt the first phosphorylation domain.