LAUSR

Hypophosphatasia (HPP) is a rare inherited genetic condition caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase, resulting in decreased alkaline phosphatase (ALP) activity. ALP deficiency leads to impaired skeletal mineralization resulting in life-threatening manifestations such as respiratory failure in severely affected infants. Children and adults may experience fractures, arthralgia, fatigue, impaired mobility, reduced quality of life, and other signs and symptoms. Severe cases are generally associated with biallelic variants. Over 400 ALPL variants associated with HPP have been described. An Alexion-sponsored genetic testing program was offered to US healthcare providers (HCPs) as a complimentary service to detect ALPL variants. HCPs were required to confirm their patients had onset of HPP-related symptoms before age 18 and lowALP levels, other signs or symptoms of HPP, and that genetic testing was medically indicated. The decision to submit a sample for genetic testing was based on the HCPs medical judgment. HCPs sent saliva or blood samples for ALPL sequencing to PreventionGenetics; variant detection was by Sanger sequencing. Deletion/duplication analysis was performed using genecentric array comparative genomic hybridization. 1113 individuals underwent genetic testing between January 15, 2018 and May 13, 2020. Overall, 775 were adults (70%) and 338 were children (30%); 763 (69%) of those tested were female. Of these, 393 individuals (35%) had a positive result [pathogenic [P] or likely pathogenic [LP] variant(s)]. There were 108 individuals (10%) with variant(s) of uncertain significance (VUS). In total, there were 522 individuals (47%) with monoallelic and 31 with biallelic ALPL variants including P, LP, and VUS variants. The five most frequently reported P/ LP variants were c.1133A>T (n = 61), c.571G>A (n = 47), c.1250A>G (n = 43), c.881A>C (n = 34), and c.346G>A (n = 12). These actionable variants represented 50% of thosewith a positive result. The five most frequently reported VUS were c.1034C>T (n = 4), c.1156G>T (n = 4), c.1253G>A (n = 4), c.1010A>G (n = 3), and c.1310C>T (n = 3). Thirtyseven novel variants were identified, of which 26 were missense. The population distribution by test outcome, cohort and sex is shown in Figure 1.While therewere 3 times asmany females tomales in the adult cohort, therewasnearequalgenderdistribution in theyoungest cohorts. Theproportionof individualswithapositive testwassimilar forchildren (37%) and adults (35%). Although not systematically reported, themost common clinical signs/symptoms were early tooth loss and skeletal fracture, and some individuals had a family history of HPP.