{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T13:38:11Z","timestamp":1781444291106,"version":"3.54.1"},"posted":{"date-parts":[[2025,11,4]]},"group-title":"Cardiovascular Medicine","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Truncating variants in the titin (\n                    <jats:italic>TTN<\/jats:italic>\n                    ) gene (TTN-TV) are the most common genetic cause of dilated cardiomyopathy (DCM) and confer a significant risk of progression to advanced heart failure (AHF). Disease penetrance of TTN-TV has been linked to the level of expression of the exon containing the TTN-TV, quantified using the percent spliced in (PSI). We hypothesized that recalculating PSI using long-read RNA sequencing and including all 15\n                    <jats:italic>TTN<\/jats:italic>\n                    isoforms would provide more accurate predictions of cardiomyopathy (penetrance) and advanced heart failure [AHF] (expressivity) in patients with TTN cardiomyopathy. Additionally, transcript and protein abundance can be discordant due to post-translational regulation in myocardium which motivated us to compare PSI values to exon-specific TTN peptide abundance.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed long-read RNA sequencing on cardiac tissue from 10 unused organ donors and 15 DCM patients and identified all\n                    <jats:italic>TTN<\/jats:italic>\n                    isoforms. We also performed mass spectrometry-based peptide mapping specific for each\n                    <jats:italic>TTN<\/jats:italic>\n                    isoform. Exon abundance was quantified using: 1) PSI-DCM-LR-15, a novel PSI metric calculated from long-read RNA sequencing which includes all 15 TTN isoforms and 2) quantile peptide intensity (QPI), a novel quantitative metric reflecting exon-specific peptide abundance. We then assessed the ability of PSI-DCM-LR-15 and QPI to predict AHF in two cohorts of patients with cardiomyopathy due to TTN-TV.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Multiple\n                    <jats:italic>TTN<\/jats:italic>\n                    transcript isoforms are expressed in myocardium. PSI-DCM-LR-15 values differed from the original PSI values, especially for the I-band. Proteomic profiling revealed discordance between mRNA and protein-level exon abundance across multiple domains, also highest for the I-band. A hybrid metric, PSI-QPI, combining transcriptional and proteomic exon abundance improved prediction of TTN-TV disease penetrance and expressivity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A novel hybrid proteogenomic metric, PSI-QPI, that incorporates both transcript and protein abundance more accurately predicts cardiomyopathy (penetrance) and AHF (expressivity) in patients with TTN-TV. This updated tool has direct clinical implications for patient management and suggests that combined proteogenomic strategies may enhance risk stratification for other genetic cardiomyopathies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is New?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>\n                          The percent spliced in (PSI) is used to quantify exon-specific mRNA abundance. This study introduces a novel PSI metric calculated using long-read RNA sequencing, PSI-DCM-LR-15, that includes all 15 titin (\n                          <jats:italic>TTN<\/jats:italic>\n                          ) isoforms. PSI-DCM-LR-15 revealed differences from the original PSI calculations, particularly in the I-band of TTN.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Proteomic analysis demonstrated significant discordance between mRNA and protein-level exon abundance. To better quantify exon abundance at the protein level, a novel metric termed quantile peptide intensity (QPI) was developed.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The authors combined PSI-DCM-LR-15 and QPI into a novel hybrid proteogenomic metric, PSI-QPI, that combined transcriptional and proteomic exon abundance. This metric improves the prediction of TTN truncating variant (TTN-TV) penetrance and expressivity.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What are the clinical implications?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Compared to the original PSI values, the PSI-QPI metric more accurately predicts which persons with TTN-TVs will develop cardiomyopathy (penetrance) and which patients with cardiomyopathy will progress to advanced heart failure (expressivity).<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>PSI-QPI can be combined with other clinical risk factors to assist clinicians in the management of patients with TTN-TVs.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          The successful application of a combined proteogenomic strategy in this study suggests that similar approaches could be used to enhance risk stratification for genes with a high frequency of truncating variants, such as desmoplakin (\n                          <jats:italic>DSP<\/jats:italic>\n                          ) and filamin C (\n                          <jats:italic>FLNC<\/jats:italic>\n                          ).\n                        <\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.02.25338804","type":"posted-content","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T21:10:22Z","timestamp":1762290622000},"source":"Crossref","is-referenced-by-count":2,"title":["Exon Proteogenomic Abundance Predicts Advanced Heart 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