3f8e9f9e736a68ddf6e6d5d6eb5704d2 322582.pdf 13b1a563151c95473c981171dfb2575cffad735d 322582.pdf f6f8dcf268a2de3ea543a5843aea1dd52e118730dc1063a71165cb74da1a5ecc 322582.pdf Title: Novel Truncating Variants in PODXL Represent a New Entity to Be Explored Among Podocytopathies Subject: Background/Objectives: Podocalyxin is a sialoprotein mainly expressed in the kidney cortex and lung tissue, which has been described as a component of the podocyte glycocalyx. This protein promotes the reorganization of the podocyte cytoskeleton, as well as the morphogenesis and differentiation of nascent podocytes, actively participating in glomerular filtration. Previous research has suggested that PODXL haploinsufficiency leads to podocytopathy with development of focal segmental glomerulosclerosis, a disorder that has been demonstrated in Podxl-deficient animal models and proposed as a primary cause in human families affected by this condition. However, only a few families have been reported, which limits the understanding about the spectrum of phenotype and prognosis of the disease. Methods: We performed high-throughput sequencing in a cohort of young adults with CKD, describing the clinical scenario of those who harbored truncating variants in the PODXL gene and testing the families for detected variants. Results: The PODXL gene exhibited a slight deviation in loss intolerance probability and moderate deviation in the observed/expected ratio of variation, which is typically observed in dominant genes with age-dependent incomplete penetrance or variable expression. We reported four novel truncating variants in the PODXL gene, along with a collection of previously published monoallelic truncating variants. Conclusions: These findings further support evidence about genetic defects in the PODXL gene associated with a new molecular entity of podocytopathy with adult onset. Additionally, the nucleotide sequence of PODXL contains particularities that require careful analysis to interpret the effect of the variants detected in this gene. Keywords: CKD 1; PODXL 2; podocytopathy 3 Author: José María García-Aznar, María Lara Besada-Cerecedo, Cristina Castro-Alonso, Milagros Sierra Carpio, Miquel Blasco, Borja Quiroga, Michal Červienka, Ricardo Mouzo, Roser Torra, Alberto Ortiz and Patricia de Sequera Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri Apr 18 09:37:20 2025 CEST ModDate: Fri Apr 18 09:41:20 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1770844 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PLOLAK+VnURWPalladioL Type 1 Custom yes yes yes 10 0 TARDTO+URWPalladioL-Roma Type 1 Custom yes yes yes 16 0 IBHRDX+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 FKMOZF+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 ZNAZEL+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 VDNGGL+CMSY10 Type 1 Builtin yes yes yes 58 0 NBLGIF+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 69 0 NBLGJF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 75 0 NBLGJG+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 81 0 NBLGJH+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 87 0 NBLGJI+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 90 0 NBLGJJ+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 93 0 NBLHBJ+PalatinoLinotype-Roman TrueType MacRoman yes yes no 96 0 NBLGIF+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 128 0 NBLGJF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 134 0 NBLGJG+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 140 0 NBLGJH+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 146 0 NBLGJI+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 149 0 NBLGJJ+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 152 0 NBLHBJ+PalatinoLinotype-Roman TrueType MacRoman yes yes no 155 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-27 04:04:47 CET RepresentationInformation: 322582.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-11-26 13:47:16 CET Size: 1770844 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 344 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Cohort Selection Destination: subsection.2.1 Item: Title: Molecular Analysis Destination: subsection.2.2 Item: Title: Review of PODXL Variants Destination: subsection.2.3 Item: Title: Results Destination: section.3 Children: Item: Title: Patient Description Destination: subsection.3.1 Item: Title: Genetic Results and Clinical Interpretation Destination: subsection.3.2 Item: Title: Cases from the Literature Destination: subsection.3.3 Item: Title: Comparative Cohort Destination: subsection.3.4 Item: Title: Limitations of the Genetic Test Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Novel Truncating Variants in PODXL Represent a New Entity to Be Explored Among Podocytopathies Author: おはびラ〠きちひロち〠ぇちひっロち〭ぁぺのちひ〬〠きちひロち〠がちひち〠あづびちつち〭ぃづひづっづつは〬〠ぃひどびぴどのち〠ぃちびぴひは〭ぁぬはのびは〬〠きどぬちでひはび〠こどづひひち〠ぃちひばどは〬〠きどぱふづぬ〠あぬちびっは〬〠あはひなち〠けふどひはでち〬〠きどっとちぬ〠ㄌづひぶどづのにち〬〠げどっちひつは〠きはふぺは〬〠げはびづひ〠ごはひひち〬〠ぁぬぢづひぴは〠くひぴどぺ〠ちのつ〠ぐちぴひどっどち〠つづ〠こづぱふづひち Subject: Background/Objectives: Podocalyxin is a sialoprotein mainly expressed in the kidney cortex and lung tissue, which has been described as a component of the podocyte glycocalyx. This protein promotes the reorganization of the podocyte cytoskeleton, as well as the morphogenesis and differentiation of nascent podocytes, actively participating in glomerular filtration. Previous research has suggested that PODXL haploinsufficiency leads to podocytopathy with development of focal segmental glomerulosclerosis, a disorder that has been demonstrated in Podxl-deficient animal models and proposed as a primary cause in human families affected by this condition. However, only a few families have been reported, which limits the understanding about the spectrum of phenotype and prognosis of the disease. Methods: We performed high-throughput sequencing in a cohort of young adults with CKD, describing the clinical scenario of those who harbored truncating variants in the PODXL gene and testing the families for detected variants. Results: The PODXL gene exhibited a slight deviation in loss intolerance probability and moderate deviation in the observed/expected ratio of variation, which is typically observed in dominant genes with age-dependent incomplete penetrance or variable expression. We reported four novel truncating variants in the PODXL gene, along with a collection of previously published monoallelic truncating variants. Conclusions: These findings further support evidence about genetic defects in the PODXL gene associated with a new molecular entity of podocytopathy with adult onset. Additionally, the nucleotide sequence of PODXL contains particularities that require careful analysis to interpret the effect of the variants detected in this gene. 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