SUN-528 The Clinical Utility of Gene Sequencing in Hypophosphatasia: Lessons from Patients with Two Rare Variants

Objectives: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity along with clinical manifestations varying from seizures to frequent fractures. Diagnosis of HPP is complicated both by its variable clinical phenotype and variable age of onset - patients are often asymptomatic well into adulthood. Although caused by variants in the ALPL gene, individual mutations are not tightly correlated with disease due to variable penetrance, expressivity, and the effect of modifier genes. In this study we sought to better understand the genotype/phenotype correlation in HPP by closely examining the clinical courses of a series of 37 patients with two rare variants in ALPL. Methods: Using BioVU, a DNA biobank that pairs patient’s genetic information with their de-identified medical record, we identified all patients that had at least one variant in ALPL. Among these patients, we chose to further study those with one of two variants. One (rs121918002) has previously been associated with disease while the other (rs148405563) was previously reported as benign. Clinical phenotypes and AlkP values were then obtained through manual review of the de-identified medical records of patients with one of these variants. Results: 20 patients with the rs121918002 (disease-associated) and 17 with the rs148405563 (benign) variant had sufficient clinical data for further analysis. None of these patients carried the diagnosis of HPP. Patients with the disease-associated variant had an average serum AlkP activity of 70.67 IU/L (SD 52.22), and 16 patients (80%) had at least one serum AlkP less than the lower limit of normal (40 IU/L). Among patients with a low AlkP, only 6 (30%) had clinical phenotypes consistent with disease. Patients with the benign variant had an average serum AlkP of 53.92 IU/L (SD 16.30) and 8 (47.1%) had at least one serum AlkP less than 40 IU/L. Among those with a low AlkP, 4 patients (23%) also had clinical phenotypes consistent with disease. Conclusions: Our study highlights the importance of clinical context to guide decisions around genetic testing in this population. In particular, genetic testing is of limited utility in those who meet clinical criteria for diagnosis. However, ALPL sequencing may be useful in younger patients with low AlkP but who do not have clinical disease. In these patients it may identify those at highest risk to go on to develop disease and assist in earlier intervention with appropriate therapy.