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.