{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T15:23:42Z","timestamp":1774452222810,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Inherited kidney diseases represent a genetically and clinically heterogeneous group of disorders affecting both pediatric and adult populations. Advances in next-generation sequencing (NGS) have improved diagnostic precision; however, genotype\u2013phenotype correlations and diagnostic yield vary substantially across disease entities. Methods:We retrospectively evaluated 165 patients referred for genetic testing due to suspected inherited kidney disease. Patients were classified into three clinical groups: polycystic kidney disease, Alport syndrome, and other syndromic patients with inherited kidney diseases. Genetic analysis was performed using NGS with Human Phenotype Ontology\u2013based gene filtering and included evaluation of both single-nucleotide variants and copy number variations. Results: Overall diagnostic yield differed markedly between groups. A molecular diagnosis was achieved in 71.4% of Alport patients, 41.0% of PKD patients, and 70.2% of patients in the Other syndromic group. In the Alport group, variants were identified exclusively in COL4A3, COL4A4, and COL4A5, with pathogenicity and gene involvement correlating with disease severity and the presence of extrarenal manifestations. The PKD group showed predominant involvement of PKD1, followed by PKHD1 and PKD2, while a substantial proportion of patients remained genetically negative, reflecting technical and biological complexity. The Other group exhibited pronounced genetic heterogeneity, with variants distributed across multiple genes involved in tubular, glomerular, metabolic, and ciliopathy-related pathways. Computational assessments demonstrated that several variants of uncertain significance (VUS) were located in functionally critical domains and were predicted to disrupt protein stability, intermolecular interactions, or conserved structural motifs, thereby supporting the biological plausibility of their potential pathogenic impact. Conclusions: Phenotype-driven NGS enables effective molecular diagnosis across diverse inherited kidney diseases while revealing disease-specific differences in diagnostic yield and genotype\u2013phenotype correlations. Systematic inclusion of variants of uncertain significance and careful integration of genetic and clinical data are essential for accurate interpretation and long-term patient management. Collectively, this study enhances understanding of inherited kidney diseases and underscores the value of integrating comprehensive genomic and computational approaches into routine nephrogenetic practice.<\/jats:p>","DOI":"10.3390\/life16030500","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:12:26Z","timestamp":1773853946000},"page":"500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotype-Driven Next-Generation Sequencing and Structure-Based In Silico Analysis Reveal Disease-Specific Diagnostic Yield and Genotype\u2013Phenotype Correlations in Inherited Kidney Diseases"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-2520","authenticated-orcid":false,"given":"Savas","family":"Baris","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Ayd\u0131n City Hospital, Aydin 09020, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9964-6383","authenticated-orcid":false,"given":"Kerem","family":"Terali","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Cyprus Health and Social Sciences University, Morphou 99750, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-431X","authenticated-orcid":false,"given":"Serdar","family":"Bozlak","sequence":"additional","affiliation":[{"name":"Department of Pediatric Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neslihan","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Ayd\u0131n City Hospital, Aydin 09020, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halil Ibrahim","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Health Sciences Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1597-5922","authenticated-orcid":false,"given":"Cuneyd","family":"Yavas","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Biruni University, Istanbul 34015, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Recep","family":"Eroz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray 68100, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-8080","authenticated-orcid":false,"given":"Mursel","family":"Hazaloglu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Ayd\u0131n City Hospital, Aydin 09020, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kubra","family":"Ozen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Ayd\u0131n City Hospital, Aydin 09020, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-9279","authenticated-orcid":false,"given":"Alper","family":"Gezdirici","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Health Sciences Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0464-6565","authenticated-orcid":false,"given":"Mustafa","family":"Dogan","sequence":"additional","affiliation":[{"name":"Division of Genetics, Gelisim Medical Laboratories, Istanbul 34100, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-507X","authenticated-orcid":false,"given":"Huseyin","family":"Kilic","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senol","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Van Training and Research Hospital, Van 65000, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-3259","authenticated-orcid":false,"given":"Ibrahim","family":"Baris","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/cge.13606","article-title":"Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system","volume":"96","author":"Rao","year":"2019","journal-title":"Clin. 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