A Mild Presentation of X-Linked Hypophosphatemia Caused by a Non-Canonical Splice Site Variant in the PHEX Gene

Author:

Fraga Gloria1,Herreros M. Alba2,Pybus Marc3,Aza-Carmona Miriam3,Pilco-Teran Melissa2,Furlano Mónica2,García-Borau M. José4,Torra Roser2,Ars Elisabet3ORCID

Affiliation:

1. Pediatric Nephrology Department, Hospital de la Santa Creu i Sant Pau, Institut de Recerca Sant Pau (IR Sant Pau), RICORS-SAMID, Universitat Autònoma de Barcelona, 08193 Barcelona, Catalonia, Spain

2. Nephrology Department, Fundació Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), Department of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Catalonia, Spain

3. Molecular Biology Laboratory, Fundació Puigvert, Institut de Recerca Sant Pau (IR-Sant Pau), RICORS2040 (Kidney Disease), 08193 Barcelona, Catalonia, Spain

4. Neonatology Unit, Pediatrics Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08193 Barcelona, Catalonia, Spain

Abstract

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.

Funder

Instituto de Salud Carlos III

Plataforma ISCIII Biobancos

RICORS program

Mecanismo para la Recuperación y la Resiliencia (MRR) and SPACKDc

Fundació la Marató de TV3

Publisher

MDPI AG

Reference18 articles.

1. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia;Haffner;Nat. Rev. Nephrol.,2019

2. X-Linked Hypophosphatemia: A New Era in Management;Dahir;J. Endocr. Soc.,2020

3. Romagnoli, C., Iantomasi, T., and Brandi, M.L. (2022). Impact of X-Linked Hypophosphatemia on Muscle Symptoms. Genes, 13.

4. Clinical utility of genetic testing in early-onset kidney disease: Seven genes are the main players;Pybus;Nephrol. Dial. Transplant.,2021

5. Predicting Splicing from Primary Sequence with Deep Learning;Jaganathan;Cell,2019

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