{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T20:13:12Z","timestamp":1769112792369,"version":"3.49.0"},"reference-count":18,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PI19\/01633"],"award-info":[{"award-number":["PI19\/01633"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PI22\/00361"],"award-info":[{"award-number":["PI22\/00361"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PI23\/00426"],"award-info":[{"award-number":["PI23\/00426"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PT20\/00196"],"award-info":[{"award-number":["PT20\/00196"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD21\/0005\/0001"],"award-info":[{"award-number":["RD21\/0005\/0001"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PMP21\/00109"],"award-info":[{"award-number":["PMP21\/00109"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["202036\u201330"],"award-info":[{"award-number":["202036\u201330"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Plataforma ISCIII Biobancos","award":["PI19\/01633"],"award-info":[{"award-number":["PI19\/01633"]}]},{"name":"Plataforma ISCIII Biobancos","award":["PI22\/00361"],"award-info":[{"award-number":["PI22\/00361"]}]},{"name":"Plataforma ISCIII Biobancos","award":["PI23\/00426"],"award-info":[{"award-number":["PI23\/00426"]}]},{"name":"Plataforma ISCIII Biobancos","award":["PT20\/00196"],"award-info":[{"award-number":["PT20\/00196"]}]},{"name":"Plataforma ISCIII Biobancos","award":["RD21\/0005\/0001"],"award-info":[{"award-number":["RD21\/0005\/0001"]}]},{"name":"Plataforma ISCIII Biobancos","award":["PMP21\/00109"],"award-info":[{"award-number":["PMP21\/00109"]}]},{"name":"Plataforma ISCIII Biobancos","award":["202036\u201330"],"award-info":[{"award-number":["202036\u201330"]}]},{"name":"RICORS program","award":["PI19\/01633"],"award-info":[{"award-number":["PI19\/01633"]}]},{"name":"RICORS program","award":["PI22\/00361"],"award-info":[{"award-number":["PI22\/00361"]}]},{"name":"RICORS program","award":["PI23\/00426"],"award-info":[{"award-number":["PI23\/00426"]}]},{"name":"RICORS program","award":["PT20\/00196"],"award-info":[{"award-number":["PT20\/00196"]}]},{"name":"RICORS program","award":["RD21\/0005\/0001"],"award-info":[{"award-number":["RD21\/0005\/0001"]}]},{"name":"RICORS program","award":["PMP21\/00109"],"award-info":[{"award-number":["PMP21\/00109"]}]},{"name":"RICORS program","award":["202036\u201330"],"award-info":[{"award-number":["202036\u201330"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["PI19\/01633"],"award-info":[{"award-number":["PI19\/01633"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["PI22\/00361"],"award-info":[{"award-number":["PI22\/00361"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["PI23\/00426"],"award-info":[{"award-number":["PI23\/00426"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["PT20\/00196"],"award-info":[{"award-number":["PT20\/00196"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["RD21\/0005\/0001"],"award-info":[{"award-number":["RD21\/0005\/0001"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["PMP21\/00109"],"award-info":[{"award-number":["PMP21\/00109"]}]},{"name":"Mecanismo para la Recuperaci\u00f3n y la Resiliencia (MRR) and SPACKDc","award":["202036\u201330"],"award-info":[{"award-number":["202036\u201330"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["PI19\/01633"],"award-info":[{"award-number":["PI19\/01633"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["PI22\/00361"],"award-info":[{"award-number":["PI22\/00361"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["PI23\/00426"],"award-info":[{"award-number":["PI23\/00426"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["PT20\/00196"],"award-info":[{"award-number":["PT20\/00196"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["RD21\/0005\/0001"],"award-info":[{"award-number":["RD21\/0005\/0001"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["PMP21\/00109"],"award-info":[{"award-number":["PMP21\/00109"]}]},{"name":"Fundaci\u00f3 la Marat\u00f3 de TV3","award":["202036\u201330"],"award-info":[{"award-number":["202036\u201330"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>X-linked hypophosphatemia (XLH) is a rare inherited disorder of renal phosphate wasting with a highly variable phenotype caused by loss-of-function variants in the PHEX gene. The diagnosis of individuals with mild phenotypes can be challenging and often delayed. Here, we describe a three-generation family with a very mild clinical presentation of XLH. The diagnosis was unexpectedly found in a 39-year-old woman who was referred for genetic testing due to an unclear childhood diagnosis of a tubulopathy. Genetic testing performed by next-generation sequencing using a kidney disease gene panel identified a novel non-canonical splice site variant in the PHEX gene. Segregation analysis detected that the consultand\u2019s father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand\u2019s son also carried this variant. RNA studies demonstrated that the non-canonical splice site variant partially altered the splicing of the PHEX gene, as both wild-type and aberrant splicing transcripts were detected in the two male members with only one copy of the PHEX gene. In conclusion, this case contributes to the understanding of the relationship between splicing variants and the variable expressivity of XLH disease. The mild phenotype of this family can be explained by the coexistence of PHEX transcripts with aberrant and wild-type splicing.<\/jats:p>","DOI":"10.3390\/genes15060679","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T03:46:56Z","timestamp":1716522416000},"page":"679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Mild Presentation of X-Linked Hypophosphatemia Caused by a Non-Canonical Splice Site Variant in the PHEX Gene"],"prefix":"10.3390","volume":"15","author":[{"given":"Gloria","family":"Fraga","sequence":"first","affiliation":[{"name":"Pediatric Nephrology Department, Hospital de la Santa Creu i Sant Pau, Institut de Recerca Sant Pau (IR Sant Pau), RICORS-SAMID, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Alba","family":"Herreros","sequence":"additional","affiliation":[{"name":"Nephrology Department, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), Department of Medicine, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Pybus","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Aza-Carmona","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Pilco-Teran","sequence":"additional","affiliation":[{"name":"Nephrology Department, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), Department of Medicine, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica","family":"Furlano","sequence":"additional","affiliation":[{"name":"Nephrology Department, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), Department of Medicine, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Jos\u00e9","family":"Garc\u00eda-Borau","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Pediatrics Department, Hospital de la Santa Creu i Sant Pau, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roser","family":"Torra","sequence":"additional","affiliation":[{"name":"Nephrology Department, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), Department of Medicine, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4118-4358","authenticated-orcid":false,"given":"Elisabet","family":"Ars","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Fundaci\u00f3 Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), 08193 Barcelona, Catalonia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41581-019-0152-5","article-title":"Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia","volume":"15","author":"Haffner","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"bvaa151","DOI":"10.1210\/jendso\/bvaa151","article-title":"X-Linked Hypophosphatemia: A New Era in Management","volume":"4","author":"Dahir","year":"2020","journal-title":"J. Endocr. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Romagnoli, C., Iantomasi, T., and Brandi, M.L. (2022). Impact of X-Linked Hypophosphatemia on Muscle Symptoms. Genes, 13.","DOI":"10.3390\/genes13122415"},{"key":"ref_4","first-page":"687","article-title":"Clinical utility of genetic testing in early-onset kidney disease: Seven genes are the main players","volume":"37","author":"Pybus","year":"2021","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.ajhg.2021.06.014","article-title":"Interpretable prioritization of splice variants in diagnostic next-generation sequencing","volume":"108","author":"Danis","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1136\/jmedgenet-2021-108013","article-title":"RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders","volume":"59","author":"He","year":"2022","journal-title":"J Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.bone.2019.01.021","article-title":"Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia","volume":"121","author":"Zhang","year":"2019","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bone.2019.05.017","article-title":"Functional analysis of 22 splice-site mutations in the PHEX, the causative gene in X-linked dominant hypophosphatemic rickets","volume":"125","author":"BinEssa","year":"2019","journal-title":"Bone"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1210\/jc.2007-1296","article-title":"Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene","volume":"93","author":"Makras","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1515\/jpem-2022-0365","article-title":"Rare PHEX intron variant causes complete and severe phenotype in a family with hypophosphatemic rickets: A case report","volume":"36","author":"Aiello","year":"2023","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1391807","DOI":"10.1155\/2022\/1391807","article-title":"X-Chromosome Inactivation and Related Diseases","volume":"2022","author":"Sun","year":"2022","journal-title":"Genet. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1111\/joim.13635","article-title":"Uncovering genetic causes of hypophosphatemia","volume":"293","author":"Puente","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/ckj\/sfx051","article-title":"Rare diseases, rare presentations: Recognizing atypical inherited kidney disease phenotypes in the age of genomics","volume":"10","author":"Ars","year":"2017","journal-title":"Clin. Kidney J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/mdc3.13165","article-title":"Challenges in Clinicogenetic Correlations: One Gene\u2014Many Phenotypes","volume":"8","author":"Magrinelli","year":"2021","journal-title":"Mov. Disord. Clin. Pr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1002\/jbmr.3955","article-title":"X-Linked Hypophosphatemia: Uniquely Mild Disease Associated with PHEX3\u2032-UTR Mutation c.*231A > G (A Retrospective Case\u2013Control Study)","volume":"35","author":"Smith","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1507\/endocrj.EJ20-0809","article-title":"A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) in X-linked hypophosphatemic rickets with mild bone phenotypes","volume":"68","author":"Asano","year":"2021","journal-title":"Endocr. J."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/6\/679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:47:42Z","timestamp":1760107662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/6\/679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,24]]},"references-count":18,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["genes15060679"],"URL":"https:\/\/doi.org\/10.3390\/genes15060679","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,24]]}}}