The ALPL gene variant project: results of the first 100 reclassified variants

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 (<i>ALPL</i>) 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 <i>ALPL</i>gene 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. <i>In vitro</i>functional testing of the variant's residual enzymatic activity and its dominant negative effect (DNE) was required for 40 variants<b>.</b>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 <i>ALPL</i>variants has resulted in a 21% increase in the number of variants in the Johannes Kepler University <i>ALPL</i>gene 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 <i>ALPL</i>variants and enable faster diagnosis and medical decision-making.

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JBMR Plus
Published
2025-03-17
DOI
https://doi.org/10.1093/jbmrpl/ziaf044
Citations
6
Primary Topic
Metabolism and Genetic Disorders
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article
Field-Weighted Citation Impact
7.91

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article

The ALPL gene variant project: results of the first 100 reclassified variants

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The ALPL gene variant project: results of the first 100 reclassified variants

Kathryn McCrystal Dahir, Catherine Rehder, Lothar Seefried, Gerald Webersinke, Jessica Ebner, Erin Huggins, Priya Sunil Kishnani, Cheryl R. Greenberg, Erica Nading, Josephine T. Tauer, Francesca Barbazza, Agnès Linglart, Eric T. Rush, Gabriel Ángel Martos‐Moreno, Mariam R. Farman, Shapour Reza Shojaei, Guillermo del Angel, Keiichi Ozono, Ahmed El‐Gazzar, Theodora Malli, Wolfgang Högler, Florian Högler
article en
6 citations

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 (<i>ALPL</i>) 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 <i>ALPL</i>gene 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. <i>In vitro</i>functional testing of the variant's residual enzymatic activity and its dominant negative effect (DNE) was required for 40 variants<b>.</b>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 <i>ALPL</i>variants has resulted in a 21% increase in the number of variants in the Johannes Kepler University <i>ALPL</i>gene 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 <i>ALPL</i>variants and enable faster diagnosis and medical decision-making.

JBMR PlusVol. 9(6)
Manitoba Health (CA), Johannes Kepler University of Linz (AT), Children's Mercy Hospital (US), University of Kansas (US), Inserm (FR), University of Würzburg (DE), Université Paris-Saclay (FR), Instituto de Salud Carlos III (ES), Health Sciences Centre (CA), Comprehensive Cancer Center Vienna (AT), Assistance Publique – Hôpitaux de Paris (FR), Chibune General Hospital (JP), AstraZeneca (Australia) (AU), Hospital Infantil Universitario Niño Jesús (ES), Centro de Investigación Biomédica en Red (ES), Kepler Universitätsklinikum (AT), Duke Medical Center (US), AstraZeneca (Japan) (JP), University of Kansas Medical Center (US), AGO Austria (AT), AstraZeneca (United States) (US), Bicêtre Hospital (FR), University of Manitoba (CA), Universidad Autónoma de Madrid (ES), University of Missouri–Kansas City (US), Medical University of Vienna (AT), Vanderbilt University Medical Center (US)
AstraZeneca, Alexion Pharmaceuticals
Peace, Justice and strong institutions
Openalex Percentile: Top 3%
Metabolism and Genetic Disorders
7.91
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