%0 Journal Article
%T New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.
%A Kishnani PS
%A Seefried L
%A Dahir KM
%A Martos-Moreno GÁ
%A Linglart A
%A Petryk A
%A Mowrey WR
%A Fang S
%A Ozono K
%A Högler W
%A Rockman-Greenberg C
%J Am J Med Genet A
%V 0
%N 0
%D 2024 Jun 17
%M 38884565
%F 2.578
%R 10.1002/ajmg.a.63781
%X Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.