Genetic characterization of a large cohort of individuals with a clinical suspicion of hypophosphatasia in the United States

Hypophosphatasia (HPP) is a rare metabolic disease resulting from variants in ALPL, inherited in an either autosomal recessive or autosomal dominant manner. Sponsored clinical ALPL testing was offered in the US for individuals with a clinical suspicion of HPP. Gene variants were assessed to determine the likelihood of identifying disease-causing variants, uncover genotype–phenotype relationships, and for further understanding of ALPL variants in the US HPP population. Variants were detected by Sanger sequencing and classified as pathogenic or likely pathogenic (P/LP; positive test result), variant(s) of uncertain significance (indeterminate test result), benign or likely benign (negative test result), or no variants (negative test result). Clinical signs/symptoms, age, sex, and family history data were voluntarily reported by participating clinicians and were explored for possible association with the test result. Of 1103 individuals tested, results were positive in 40 %, indeterminate in 5 %, and negative in 55 %. Most positive tests were monoallelic P/LP variants (n = 413). The most frequently identified P/LP variants were c.1133A > T/p.Asp378Val (n = 61), c.571G > A/p.Glu191Lys (n = 47), and c.1250A > G/p.Asn417Ser (n = 44). In total, 23 novel ALPL variants were identified, of which 43 % were P/LP and the most frequent type was missense (74 %). Among the 25 % of participants for whom signs/symptoms were reported, a significant association was observed for those with a family history of HPP signs/symptoms and a positive test result. These data contribute important information on the likelihood of disease-causing ALPL variants in individuals with clinical signs/symptoms of HPP, the importance of family history in HPP testing, distribution of ALPL variants, and identification of novel ALPL variants.