{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T02:03:58Z","timestamp":1784081038323,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal resistance to arginine vasopressin, most commonly caused by pathogenic variants in the AVPR2 gene. While X-linked NDI classically affects males, heterozygous females may exhibit variable clinical expression. Certain AVPR2 variants are associated with partial NDI and milder phenotypes. Methods: We conducted a retrospective family study of a multigenerational Greek pedigree with suspected hereditary NDI. Clinical, biochemical, and pedigree data were collected through chart review and family interviews. Genetic analysis was performed using whole-exome sequencing, and variant interpretation followed ACMG\/AMP guidelines. Results: Fourteen individuals across four generations were evaluated. Molecular analysis identified a familial AVPR2 (NM_000054.7):c.964C&gt;T (p.Pro322Ser) missense variant in three males and three females, with obligate carrier status inferred in two deceased females, segregating in an X-linked pattern. Hemizygous males exhibited a broad phenotypic spectrum, ranging from partial NDI with later onset to severe early-onset disease with urinary tract complications. Heterozygous females showed variable expression, from asymptomatic carriers to mildly symptomatic individuals. The variant co-segregated with disease and, based on ACMG criteria, it was classified as pathogenic. Conclusions: In our family, the AVPR2 c.964C&gt;T (p.Pro322Ser) variant was associated with a remarkably broad clinical spectrum, ranging from asymptomatic heterozygous females to severe early-onset disease with urinary tract complications in affected males. These observations emphasize the need for early molecular diagnosis, systematic evaluation of female carriers, and long-term surveillance to prevent disease-related complications and optimize genetic counselling.<\/jats:p>","DOI":"10.3390\/jcm15145514","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"5514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["X-Linked Nephrogenic Diabetes Insipidus Associated with the AVPR2 c.964C&gt;T (p.Pro322Ser) Variant: A Family Case Series"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3043-4917","authenticated-orcid":false,"given":"Kalliopi","family":"Vardaki","sequence":"first","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"},{"name":"Department of Pediatrics, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-9823","authenticated-orcid":false,"given":"Ioannis","family":"Petrakis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Drosataki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8123-771X","authenticated-orcid":false,"given":"Christos","family":"Pleros","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadni","family":"Androvitsanea","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Lygerou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kleio","family":"Dermitzaki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonakis","family":"Andreas","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kydonaki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-9421","authenticated-orcid":false,"given":"Kostas","family":"Stylianou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Heraklion University Hospital, 71500 Iraklio, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1242\/jeb.200.2.295","article-title":"Role of the Ca2+-sensing receptor in divalent mineral ion homeostasis","volume":"200","author":"Hebert","year":"1997","journal-title":"J. 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