8447445d02353ebb8fb2cc05c644bc85 306339.pdf c5e8808519b403b3b1a84f0f7867ac7a1f327488 306339.pdf 3aeadb2a775ce4148f4c794332572228c42c9a8d55bb7f67c9a8b73ec1408b8d 306339.pdf Title: A Mild Presentation of X-Linked Hypophosphatemia Caused by a Non-Canonical Splice Site Variant in the PHEX Gene Subject: 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’s father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand’s 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. Keywords: X-linked hypophosphatemia; PHEX gene; non-canonical splice site variant Author: Gloria Fraga, M. Alba Herreros, Marc Pybus, Miriam Aza-Carmona, Melissa Pilco-Teran, Mónica Furlano, M. José García-Borau, Roser Torra and Elisabet Ars Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri May 24 07:30:32 2024 CEST ModDate: Fri May 24 08:07:28 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 6 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 520859 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- XWOCXD+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 FNGHUX+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 KJDCGB+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 GIEJDS+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 TWGOWA+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 CIQLLF+VnURWPalladioL Type 1 Custom yes yes yes 37 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 53 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 56 0 VZQAMK+CMSY10 Type 1 Builtin yes yes yes 73 0 OVNEXW+EURM10 Type 1 Builtin yes yes yes 78 0 XIRVNA+EURB10 Type 1 Builtin yes yes yes 86 0 BPEPPH+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 97 0 BPEPPI+PalatinoLinotype CID TrueType Identity-H yes yes yes 100 0 BPEPPJ+PalatinoLinotype TrueType WinAnsi yes yes no 106 0 BPEPPL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 109 0 BPFANI+PalatinoLinotype TrueType MacRoman yes yes no 112 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-17 16:58:16 CET RepresentationInformation: 306339.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-11 09:59:13 CET Size: 520859 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 209 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Item: Title: Results Destination: section.3 Children: Item: Title: Clinical Description Destination: subsection.3.1 Item: Title: Genetic Study Destination: subsection.3.2 Item: Title: Discussion Destination: section.4 Item: Title: References Destination: section.5 Info: Title: A Mild Presentation of X-Linked Hypophosphatemia Caused by a Non-Canonical Splice Site Variant in the PHEX Gene Author: Gloria Fraga, M. Alba Herreros, Marc Pybus, Miriam Aza-Carmona, Melissa Pilco-Teran, Mónica Furlano, M. José García-Borau, Roser Torra and Elisabet Ars Subject: 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’s father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand’s 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. 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