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Although the type of ADPKD variant can influence disease severity, rare, hypomorphic\n                      <jats:italic>PKD1<\/jats:italic>\n                      variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic\n                      <jats:italic>PKD1<\/jats:italic>\n                      variants contribute to ADPKD phenotypic outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the prevalence of rare, additional, potentially protein-altering\n                      <jats:italic>PKD1<\/jats:italic>\n                      variants in patients with\n                      <jats:italic>PKD1<\/jats:italic>\n                      -associated ADPKD\n                      <jats:italic>.<\/jats:italic>\n                      The association between rare, additional, potentially protein-altering variants and phenotypic outcomes, including progression to kidney failure, age at onset of hypertension and urological events, height-adjusted total kidney volume, and predicting renal outcomes in PKD (PROPKD) score, were examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rare, additional, potentially protein-altering variants were detected in 6% of the 932 ADPKD patients in the study. The presence of rare, additional, potentially protein-altering variants was associated with 4\u00a0years earlier progression to kidney failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18\u20132.34;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.003), with in-\n                      <jats:italic>trans<\/jats:italic>\n                      rare, additional, potentially protein-altering variants (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200913\/894) showing a greater risk of kidney failure (HR: 1.83; 95% CI 1.00\u20133.33;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.049). We did not detect statistically significant differences between rare, additional, potentially protein-altering variants and other phenotypic outcomes compared to those without rare, additional, potentially protein-altering variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In patients with\n                      <jats:italic>PKD1<\/jats:italic>\n                      -associated ADPKD, our findings suggest that rare, additional, potentially protein-altering variants in\n                      <jats:italic>PKD1<\/jats:italic>\n                      may influence disease severity. These findings have potential clinical implications in counselling and treating patients with rare, additional, potentially protein-altering variants, but further investigation of such variants in larger, longitudinal cohorts with detailed, standardised phenotype data is required.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s40620-025-02211-x","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T08:47:58Z","timestamp":1738226878000},"page":"1457-1467","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease"],"prefix":"10.1093","volume":"38","author":[{"given":"Elhussein A. 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