X-linked hypophosphatemia (XLH), an X-linked dominant disorder caused by a pathogenic change (variant) in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. The program provides a no-cost test to confirm a clinical XLH diagnosis or to aid diagnosis of suspected XLH or other genetic hypophosphatemia.
Methods Program eligibility criteria: >/=1y old and either clinical XLH diagnosis (confirmatory) or suspicion of XLH/ genetic hypophosphatemia (suspected) as evidenced by 2 or more clinical signs/ symptoms. The next generation sequencing gene panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant (CNV) detection was performed.
Results 317 unrelated probands have been tested as of October 2, 2019. Of 158 XLH confirmatory samples received, 143 (90.5%) had a PHEX variant: 14 (9.8%) were variants of uncertain significance (VUS) and 129 (90.2%) were either pathogenic or likely pathogenic (P/LP) XLH molecular diagnoses. Of the 15 patients (9.5%) where no PHEX variant was found, one had a P variant in FGF23 (autosomal dominant hypophosphatemic rickets molecular diagnosis) and another had P and LP variants in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2 molecular diagnosis). Of 159 suspected samples, 101 (63.5%) had a PHEX variant: 14 (13.9%) were variants of uncertain significance (VUS) and 87 (86.1%) were P/LP (XLH molecular diagnoses). No PHEX variant was found for 58 (36.5%) of suspected samples; however, 5 of these had other findings: a dominant-negative heterozygous P variant for ALPL was detected in 3 samples (3 hypophosphatasia, HPP, molecular diagnoses); a fourth carried two P variants in ALPL; a fifth had a LP variant and a VUS in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2). Of 121 unique P/LP PHEX variants detected, 59 were deletions duplications or insertions. A complex rearrangement and an Alu-mediated insertion were detected in the full cohort. To date, additional family member testing was performed for 10 probands with original VUS: in 4 cases the VUS was reclassified to P/LP; 2 were reclassified to P/LP due to more clinical info, highlighting the value of family testing and clinical info to resolve VUS. RNA analyses to resolve VUS and unidentified variants may further improve molecular diagnoses of genetic hypophosphatemia. Program results demonstrate a high diagnostic yield for confirmatory and suspected XLH/ genetic hypophosphatemia.