HYPOPHOSPHATEMIC RICKETS

PHEX, FGF23, DMP1ENPP1 AND SLC34A3 GENE ANALYSIS IN HYPOPHOSPHATAEMIC RICKETS

Hypophosphatemic rickets (HR) is characterised by childhood rickets, short stature, dental anomalies, osteomalacia, osteoarthritis and hearing problems. Biochemically affected individuals have hypophosphatemia (low serum phosphate) due to decreased renal tubular reabsorption, phosphaturia (high urine phosphate) and decreased or inappropriately normal serum calcitriol (1,25-dihydroxyvitamin D) levels.

The X linked dominant form (XLH) is caused by disease-causing variants in the PHEX gene (The HYP consortium 1995 Nat Genet 11, 130-136; Holm et al 1997 Am J Hum Genet 60, 790-797). Variants are found in 87% of familial cases and 73% of sporadic cases (Gaucher et al 2009 Hum Genet 125, 401-411).

The autosomal dominant form (ADHR) is caused by gain of function variants in the FGF23 gene. The reported missense variants affect the arginine residues at codon 176 and 179 in the proteolytic cleavage domain (ADHR consortium 2000 Nat Genet 26, 345-348). Loss of function variants throughout the FGF23 gene also cause Hyperphosphatemic Familial Tumoral Calcinosis (HFTC).

The autosomal recessive form (ARHR) is caused by variants in the DMP1 (ARHR type 1) (Lorenz-Depiereux et al 2006 Nat Genet 38, 1248-1250) or ENPP1 (ARHR type 2) genes (Lorenz-Depiereux et al 2010 Am J Hum Genet 86, 267-272). Disease-causing variants in the ENPP1 gene also cause Generalised Arterial Calcification of infancy (GACI).

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.