Document Type

Article

Publication Date

11-2025

Identifier

DOI: 10.1002/jimd.70083; PMCID: PMC12497681

Abstract

Hypophosphatasia (HPP) is a rare, inherited monogenic disorder that is typically caused by variants in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Genetic testing for ALPL variant(s) to confirm the diagnosis in patients with suspected HPP is a standard practice based on availability. This review attempts to improve the current understanding of the genetics of HPP as it addresses five key related topics: (1) HPP patterns of inheritance and the relationship between HPP genotype and phenotype, (2) how the disease can manifest (including specific genotypes) in heterozygotes, (3) potential reasons why some patients have persistently low alkaline phosphatase activity yet lack an ALPL variant, (4) the implications of and resources for variants of uncertain significance (VUS), and (5) recent information on genetic testing in fetuses and newborns. We summarize pertinent information applicable in daily clinical practice, with the objective of preventing missed, delayed, or incorrect HPP diagnoses and improving patient care.

Journal Title

Journal of inherited metabolic disease

Volume

48

Issue

6

First Page

70083

Last Page

70083

MeSH Keywords

Humans; Hypophosphatasia; Alkaline Phosphatase; Genetic Testing; Genotype; Phenotype; Infant, Newborn; Mutation

PubMed ID

41047464

Keywords

alkaline phosphatase; bone mineralization; dominant‐negative effect; genetic counseling; genetic screening; genetic testing; genome sequencing; genotype; phenotype; vitamin B6

Comments

Grants and funding

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

Publisher's Link: https://onlinelibrary.wiley.com/doi/10.1002/jimd.70083

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