SUN-717 Low Penetrance of Hypophosphatasia in Asymptomatic Individuals Carrying Heterozygous ALPL Variants

Abstract Disclosure: K.M. Dahir: Alexion Pharmaceuticals, Inc., Ultragenyx, Kyowa Kirin. J. Liu: None. A. Javid: None. G. Wang: None. L. Bastarache: None. Hypophosphatasia (HPP) is a rare, inherited multisystem disorder caused by pathologic variants in the gene ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Homozygous or compound heterozygous ALPL mutations often result in severe HPP, while heterozygous mutations are more likely to manifest in modest, mild or even asymptomatic disease. Asymptomatic HPP patients and their physicians are typically unaware of disease manifestations. Most often asymptomatic HPP is detected at random or during cascade testing, and the genetic and molecular determinants of asymptomatic HPP remain poorly understood. For this study, we postulated low penetrance as an important contributor to asymptomatic HPP. To test this hypothesis, HPP diagnostic criteria, as recently put forth by the International Working Group on HPP, were used to survey asymptomatic individuals carrying pathologic or likely-pathologic ALPL variants (ALPL+). The study was conducted under Vanderbilt University IRB protocol #222309 and identified 70 ALPL+ individuals, along with 148 age- and sex-matched ALPL wild type controls (ALPL-), in BioVU, a large biorepository linking genomic samples to de-identified electronic health records (EHR) and thus allowing for retrospective diagnosis of HPP. Diagnostic criteria were met if ALPL+ individuals had low ALP and femur/metatarsal fractures, or in the absence of femur/metatarsal fractures, at least two of the following: abnormal gait, weakness, chondrocalcinosis, arthritis, joint stiffness, early dental loss or calcium/phosphorus disorder (MSK). Of the 70 ALPL+ individuals, 44 patients had MSK involvement, however only 18.2% (8/44) met the diagnostic criteria for HPP, while a majority of 81.8% (36/44) did not meet diagnostic criteria for HPP. The remaining 26 patients without MSK involvement all did not meet diagnostic criteria for HPP. MSK features showed significant differences in the ALPL+ group (p=0.02). The overall penetrance rate for those in the ALPL+ group was only 12.9%. Kaplan-Meier Survival curve analysis showed a trend to earlier mobility impairment in the ALPL+ group whereas there was no significant difference in disease burden such as arthritis and fatigue. Unexpectedly, 5 patients (3.4%) in the ALPL- control group were diagnosed with HPP, possibly due to unidentified variants or non-ALPL genetic factors. Together, the data confirms our hypothesis and may help to refine classification, diagnostic criteria, and treatment decisions for HPP. Presentation: Sunday, July 13, 2025