{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:18:58Z","timestamp":1777393138055,"version":"3.51.4"},"reference-count":122,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nephrocalcinosis, defined as the deposition of calcium salts within the renal parenchyma, represents a radiologic and pathologic endpoint shared by a broad spectrum of metabolic and monogenic disorders. Advances in genomic medicine have identified more than 30 genes involved in tubular transport, mineral and acid\u2013base homeostasis, oxalate metabolism, mitochondrial function, ciliary signaling, and nephron development, reframing nephrocalcinosis as a heterogeneous manifestation of discrete molecular defects rather than a single disease entity. Despite this diversity, these conditions converge on common physicochemical pathways of tubular supersaturation, crystal nucleation, growth, and intrarenal retention. These processes are amplified by the intrinsic vulnerability of the renal medulla\u2014characterized by hyperosmolality, hypoxia, and slow tubular flow\u2014and by epithelial injury, loss of crystallization inhibitors, and impaired ciliary signaling. Distinct genotype\u2013phenotype signatures, including age at onset, biochemical profiles, and extrarenal manifestations, provide important diagnostic clues and help differentiate major monogenic entities. The increasing availability of targeted gene panels, whole-exome sequencing, and whole-genome sequencing has substantially improved diagnostic yield, particularly in pediatric populations. Molecular diagnosis now directly informs therapeutic decision-making and long-term management, enabling a shift toward precision nephrology. This narrative review integrates genetic, mechanistic, and clinical perspectives to illustrate how molecular diagnosis reshapes the evaluation, prognosis, and treatment of nephrocalcinosis.<\/jats:p>","DOI":"10.3390\/ijms27083616","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"3616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular and Genetic Determinants of Nephrocalcinosis: Mechanisms, Genotype\u2013Phenotype Correlations, and Precision Medicine"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0743-6777","authenticated-orcid":false,"given":"Setalia","family":"Popa","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Ia\u0219i, Romania"},{"name":"Clinica Sante, C3 Ion Baiesu Street, 120072 Buzau, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-6035","authenticated-orcid":false,"given":"Andrei Cristian","family":"Gr\u0103dinaru","sequence":"additional","affiliation":[{"name":"\u201cIon Ionescu de la Brad\u201d Iasi University of Life Sciences, 3 Sadoveanu Alley, 700490 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3279-0492","authenticated-orcid":false,"given":"Elena Emanuela","family":"Braha","sequence":"additional","affiliation":[{"name":"\u201cC.I. Parhon\u201d National Institute of Endocrinology, 34\u201336 Aviatorilor Blvd, Sector 1, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihaela","family":"Gr\u0103mescu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramona","family":"Babici","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Ailenei","sequence":"additional","affiliation":[{"name":"Clinica Sante, C3 Ion Baiesu Street, 120072 Buzau, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-4244","authenticated-orcid":false,"given":"L\u0103cr\u0103mioara Ionela","family":"Butnariu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Ia\u0219i, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1093\/ndt\/gfaf062","article-title":"Kidney stone biology: Insights from genetics","volume":"40","author":"Spasiano","year":"2025","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"F1243","DOI":"10.1152\/ajprenal.00211.2016","article-title":"Genetic, pathophysiological, and clinical aspects of nephrocalcinosis","volume":"311","author":"Oliveira","year":"2016","journal-title":"Am. J. Physiol. Ren. 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