Proteomics Uncovers Cryptic JPH2 Loss in Paediatric Dilated Cardiomyopathy

The research focused on using proteomics as a diagnostic tool for pediatric dilated cardiomyopathy (DCM), whose genetic diagnosis remains low despite advances in sequencing. Scientists analyzed left ventricular myocardial samples from pediatric patients undergoing heart transplantation. In one patient, they found a heterozygous frameshift variant in the JPH2 gene, but proteomic analysis revealed pronounced downregulation of JPH2 protein, suggesting biallelic loss-of-function. Further analysis of genomic data revealed a large inversion of approximately 8.34 Mb with a breakpoint in intron 5 of JPH2 that displaced the 3'UTR from the coding sequence. Both variants were confirmed to be in trans using long-read DNA sequencing. RNA sequencing showed that transcripts containing 3'UTR were reduced to approximately 10% compared to controls. This study represents the first use of proteomics from explanted cardiac tissue for genetic diagnosis.