New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.

Autor: Kishnani PS; Duke University Medical Center, Durham, North Carolina, USA., Seefried L; University of Würzburg, Würzburg, Germany., Dahir KM; Vanderbilt University Medical Center, Nashville, Tennessee, USA., Martos-Moreno GÁ; Hospital Infantil Universitario Niño Jesús, IIS La Princesa, Universidad Autónoma de Madrid, CIBERobn, ISCIII, Madrid, Spain., Linglart A; Paris-Saclay University, AP-HP and INSERM, Paris, France., Petryk A; Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, USA., Mowrey WR; Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, USA., Fang S; Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, USA., Ozono K; Iseikai International General Hospital, Kita Ward, Osaka, Japan., Högler W; Johannes Kepler University Linz, Linz, Austria., Rockman-Greenberg C; University of Manitoba, Winnipeg, Manitoba, Canada.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Nov; Vol. 194 (11), pp. e63781. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1002/ajmg.a.63781
Abstrakt: 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.
(© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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