OR13-3 Hypophosphatemia Gene Panel Sponsored Program: A High Yield of Molecular Diagnoses from Clinically Confirmed XLH and Suspected Genetic Hypophosphatemia

Abstract

Abstract Introduction X-linked hypophosphatemia (XLH), a dominant disorder caused by disease-associated variants 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, fractures and poor fracture healing, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. The Hypophosphatemia Gene Panel Sponsored Program provides a no-charge genetic test to patients to confirm a clinical XLH diagnosis or to aid in the diagnosis of suspected genetic hypophosphatemia. Methods Individuals aged ≥6 months with either a clinical XLH diagnosis or suspicion of genetic hypophosphatemia, as evidenced by 2 or more clinical signs/ symptoms, were eligible for testing. The next generation sequencing panel includes 17 genes: ALPL, CLCN5, CTNS, ​​​​CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, GNAS, OCRL, PHEX, SLC34A1, SLC34A3, and VDR. Copy number variant (CNV) detection was also performed. Variants were interpreted according to the joint consensus from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology using Invitae's proprietary point-based scoring system, Sherloc. In all analyses, data were summarized using descriptive statistics. Results One thousand six hundred sixty-eight unrelated individuals, ages 6 months to 87 years (mean = 27.4±21.2 years, median = 22.5 years), were tested between 27 February 2019 and 23 October 2021. The majority of individuals were female (66.6%) and of self-reported White ancestry (54.9%). Eight hundred seventy-nine (52.7.%) unrelated individuals had a PHEX variant: 825 (93.9%) were either pathogenic or likely pathogenic (P/LP) and 54 (6.1%) were variants of uncertain significance (VUS). Of the 789 (47.3%) cases where no PHEX P/LP or VUS was found, 116 (14.7%) had molecular diagnoses associated with other genes/disorders: ALPL (71 with 1 variant, 12 with 2 variants), FGF23 (8), CYP27B1 (14), SLC34A3 (5), and two or fewer molecular diagnoses for DMP, CTNS, ENPP1, and OCRL. Four hundred and twenty-eight unique P/LP PHEX variants were detected: 136 deletions, duplications or insertions ​(<100 bp)​; 41 copy number variants ​(>100 bp); 74 splice-site variants; 177 single nucleotide variants. Additional family member testing/clinical information/observation of variants resulted in 25 VUS being reclassified to P/LP (impacting 50 individuals), highlighting the value of cascade family testing/clinical information to resolve VUS. Notably, the frequency of PHEX VUS has decreased from 8.9% in 2019 (41 weeks) to 4.4% in 2021 (44 weeks). Conclusions The frequency of any PHEX variant classified as VUS has decreased more than two-fold since 2019. RNA analyses to resolve VUS may further improve molecular diagnostic yield. Program results provide a high molecular diagnostic yield for XLH and other genetic hypophosphatemia disorders and new insight into XLH-associated PHEX variants. Presentation: Sunday, June 12, 2022 11:30 a.m. - 11:45 a.m.