Clinical and Molecular Genetic Characteristics of Patients with Hereditary Hypophosphatemia

Abstract

Context: Hereditary hypophosphatemia (HH), is a rare condition related to decreased renal tubular phosphate reabsorption. Although X-linked hypophosphatemia or PHEX gene variant is the most frequent cause of HH, recent advances in next-generation sequencing (NGS) techniques enable the identification of genetic etiologies as a whole.

Objective: This work aimed to identify genetic causes of HH using various genetic testing methods and to compare clinical features between FGF23-dependent and FGF23-independent HH groups.

Methods: Fifty patients (24 males) from 39 unrelated families were included. Based on initial evaluation, PHEX gene sequencing was performed in patients with clinical and biochemical findings suggestive of FGF23-dependent HH. If sequencing showed no alterations, multiplex ligation-dependent probe amplification (MLPA) analysis for PHEX was conducted. Initially, a specific gene panel was performed for FGF23-independent HH or those in whom the PHEX gene showed no genetic alteration.

Results: Genetic etiology was revealed in 43 patients from 33 families. PHEX gene variants (4 novel) were identified in 24 patients from 19 unrelated families (50%). SLC34A3 was the second most common (16.6%) and the rest were rarer causes of hypophosphatemia (DMP1 n = 3, SLC34A1 n = 2, CLCN5 n = 2, OCRL n = 2, FAM20C n = 1, SLC2A2 n = 1). When the genetically proven FGF23-dependent (n = 28) and FGF23-independent (n = 15) HH groups were compared for clinical and biochemical features; lower phosphate and TmP/GFR SDSs and higher ALP SDS with more severe clinical rickets were detected in FGF23-dependent group, whereas higher serum and urine calcium and lower PTH levels were detected in FGF23-independent group.

Conclusion: The application of MLPA provided an additional explanatory value of 10% to the molecular etiology. However, 10% of the cases of HH still remain unexplained even after a comprehensive genetic work-up. Biochemical findings suggest distinct biochemical profiles between FGF23-dependent and FGF23-independent HH groups.

Keywords: CLCN5; PHEX; SLC34A1; SLC34A3; hereditary hypophosphatemia; rickets.