Document Type

Article

Publication Date

6-2025

Identifier

DOI: 10.1093/jbmrpl/ziaf044; PMCID: PMC12083982

Abstract

Hypophosphatasia (HPP) is an inherited disorder that affects bone and tooth mineralization, among other body systems. HPP is caused by pathogenic variants in the alkaline phosphatase-liver (ALPL) gene, which encodes tissue nonspecific alkaline phosphatase. One major challenge in diagnosing HPP is interpreting variant of uncertain significance (VUS), which can create uncertainty for patients and healthcare professionals, leading to delays in diagnosis and treatment or incorrect diagnoses. Since February 2021, the ALPLgene variant consortium has reclassified 100 VUS using adjusted American College of Medical Genetics/Association for Molecular Pathology criteria. Of these, 11 were reclassified as pathogenic, 62 as likely pathogenic, three as likely benign, one as benign, and 23 remained as VUS; out of 100 variants, there were 81 missense, eight frameshifts, four in-frame deletions, two intronic, two synonymous, two nonsense, and one splice site variant. In vitrofunctional testing of the variant's residual enzymatic activity and its dominant negative effect (DNE) was required for 40 variants.Out of 40 variants tested, 72% showed < 30% residual activity and were reclassified as pathogenic or likely pathogenic. Among these, 48% exhibited a DNE. All variants with ˂15% residual activity showed a DNE, while those with over 20% did not. In terms of domains, all tested variants in the active site domain and 75% of those in the homodimeric interface showed < 30% residual activity. The consortium's reclassification of 100 ALPLvariants has resulted in a 21% increase in the number of variants in the Johannes Kepler University ALPLgene variant database. Furthermore, 136 new genotypes with 118 associated phenotypes, including asymptomatic states, have been added. These expanded resources will help improve genetic counseling for patients and families affected by ALPLvariants and enable faster diagnosis and medical decision-making.

Journal Title

JBMR Plus

Volume

9

Issue

6

First Page

044

Last Page

044

PubMed ID

40386289

Keywords

ACMG; alkaline phosphatase; hypophosphatasia; reclassification; rickets; vitamin b6

Comments

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://academic.oup.com/jbmrplus/article/9/6/ziaf044/8081574?login=false

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