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

• Published in: Journal of bone and mineral research Vol. 28; no. 6; pp. 1378 - 1385
• Main Authors: Rafaelsen, Silje Hjorth, Ræder, Helge, Fagerheim, Anne Kristine, Knappskog, Per, Carpenter, Thomas O, Johansson, Stefan, Bjerknes, Robert
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2013
• Subjects: Adolescent; Adult; Calcinosis - genetics; Calcinosis - metabolism; Calcinosis - pathology; Casein Kinase I; Cellular biology; DNA Mutational Analysis; Exome; EXOME SEQUENCING; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; FAM20C; FAMILIAL HYPOPHOSPHATEMIA; Female; FGF23; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Humans; Hypophosphatemia, Familial - genetics; Hypophosphatemia, Familial - metabolism; Hypophosphatemia, Familial - pathology; Male; Medical research; Mutation; Norway; Osteosclerosis - genetics; Osteosclerosis - metabolism; Osteosclerosis - pathology; RAINE SYNDROME; Tooth Abnormalities - genetics; Tooth Abnormalities - metabolism; Tooth Abnormalities - pathology; Norway
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1002/jbmr.1850

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.