ESPE Yearbook of Paediatric Endocrinology

In brief: This article describes the functionalities of the Global ALPL gene variant classification project, which aims to reclassify variants of uncertain significance (VUS) in the ALPL gene and to continuously assess and update genetic, phenotypic, and functional variant information in hypophosphatasia.

Commentary: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the alkaline phosphatase ( ALPL ) gene, which encodes the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Low alkaline phosphatase activity is associated with impaired mineralisation of the skeleton, manifested by signs of rickets and osteomalacia, as well as extraskeletal manifestations (such as failure to thrive, seizures, muscle weakness, gross motor delay, abnormal gait, pain, early loss of primary teeth, and other dental problems).

Diagnosis of the disease is based on a combination of clinical and radiographic signs, laboratory profile and the identification of a pathogenic or likely pathogenic variant in the ALPL gene. Analysis of the ALPL gene is therefore an important step in the diagnostic process, but variants of uncertain significance (VUS) can cause diagnostic delay and uncertainty for patients and healthcare providers.

In 2021, the Global ALPL Gene Variant Classification Project was established to reclassify VUS in the ALPL gene and to continuously assess and update genetic, phenotypic, and functional variant information in hypophosphatasia. To this end, the database provides a submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts was established to reclassify the submitted VUS using a multi-step process including a clinical phenotype assessment, in-depth literature review, molecular genetic assessment, and in-vitro functional testing of variants in a cotransfection model to measure ALP residual activity.

This classification project will help to define the milder range of the disease, but also to characterise new and existing HPP phenotypes, leading to improved care for these patients.