Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23–related hypophosphatemia, dental anomalies, and ectopic calcification

Authors

  • Silje Hjorth Rafaelsen MD,

    Corresponding author
    1. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    • Department of Clinical Medicine, University of Bergen, Bergen, Norway
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  • Helge Ræder,

    1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
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  • Anne Kristine Fagerheim,

    1. Medical Department, Nordland County Hospital, Bodø, Norway
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  • Per Knappskog,

    1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
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  • Thomas O Carpenter,

    1. Departments of Pediatrics (Endocrinology) and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
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  • Stefan Johansson,

    1. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    2. Department of Biomedicine, University of Bergen, Bergen, Norway
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  • Robert Bjerknes

    1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
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Address correspondence to: Department of Clinical Medicine, Section for Pediatrics, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: silje.rafaelsen@pedi.uib.no

ABSTRACT

Fibroblast growth factor 23 (FGF23) plays a crucial role in renal phosphate regulation, exemplified by the causal role of PHEX and DMP1 mutations in X-linked hypophosphatemic rickets and autosomal recessive rickets type 1, respectively. Using whole exome sequencing we identified compound heterozygous mutations in family with sequence similarity 20, member C (FAM20C) in two siblings referred for hypophosphatemia and severe dental demineralization disease. FAM20C mutations were not found in other undiagnosed probands of a national Norwegian population of familial hypophosphatemia. Our results demonstrate that mutations in FAM20C provide a putative new mechanism in human subjects leading to dysregulated FGF23 levels, hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis of the long bones in the absence of rickets.

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