ESPE2023 Free Communications Bone, Growth Plate and Mineral Metabolism (6 abstracts)
First Results of the Global ALPL Gene Variant Classification Project
Mariam R Farman 1 , Catherine Rehder 2 , Theodora Malli 3 , Cheryl Rockman-Greenberg 4 , Kathryn Dahir 5 , Gabriel Ángel Martos-Moreno 6,7 , Agnès Linglart 8 , Keiichi Ozono 9 , Lothar Seefried 10 , Guillermo del Angel 11 , Florian Högler 1 , Francesca Barbazza 1 , Lisa K John 1 , Sewmi M. A. Delana Mudiyanselage 1 , Erica Burner Nading 2 , Erin Huggins 2 , Eric T Rush 12 , Ahmed El-Gazzar 1 , Priya S Kishnani 13 , Gerald Webersinke 3 & Wolfgang Högler 1
1Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria. 2Duke University Medical Center, Division of Medical Genetics, Department of Pediatrics, Durham, USA. 3Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria. 4Department of Pediatrics and Child Health Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. 5Vanderbilt University Medical Center, Program for Metabolic Bone Disorders, Nashville, USA. 6 Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, IIS La Princesa, Madrid, Spain. Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain. 7CIBER Fisiopatología de la Obesidad y Nutrición. ISCIII, Madrid, Spain. 8AP-HP, Paris Saclay University, INSERM, Bicêtre Paris Saclay hospital, Le Kremlin-Bicêtre, France. 9Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. 10Julius-Maximilian University, Würzburg, Germany. 11Alexion, AstraZeneca Rare Disease, Boston, USA. 12Division of Clinical Genetics, Children's Mercy Hospital Kansas City, Kansas City, MO, USA; Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA; Department of Pediatrics, University of Missouri – Kansas City School of Medicine, Kansas, USA. 13Duke University Medical Center, Division of Medical Genetics, Department of Pediatrics, Durham, USA
Background: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase. A major challenge in diagnosing HPP is interpreting variants in ALPL classified as variants of uncertain significance (VUS) according to ACMG/AMP criteria, creating uncertainty in patients and treating physicians resulting in diagnostic delays.
Objectives: The ALPL gene variant classification project was established to reclassify VUS and to continuously assess and update genetic, phenotypic, and functional variant information in the ALPL gene variant database (https://alplmutationdatabase.jku.at/), an open-access archive for interpretations of the clinical significance of variants reported in ALPL. We aim to report the first results of newly classified variants in this project.
Methods: An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature review including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing (episomal pcDNA3 vectors used in a co-transfection model to express a variant in renal MDCK-II cells to measure ALP residual activity and assess dominant negative effect).
Results: Currently, the ALPL database has 423 variants and 587 genotypes. The number of VUS reclassified/classified by the ALPL gene consortium since its inception in Feb 2021 is 51, as shown in the table below.
| Variants | Number of Variants |
| Reclassified to date | 51 |
| -Reclassified with functional testing | 25 |
| -Reclassified from literature | 7 |
| New submissions classified | 19 |
Out of the 51 classified or reclassified variants, 3 were pathogenic, 24 likely pathogenic, 2 were likely benign, 1 benign, and 21 remained VUS. 68 new genotypes and 50 new phenotypes were added to the variants in the ALPL database. Through studying the submitted and reported phenotypes, we discovered distinct new phenotypes - asymptomatic heterozygote individuals featuring the typical biochemical signature of HPP (c.1225C>T, c.466C>T, c818C>T, c.244G>A, c.244G>C, c.906C>A, c.83A>G and c.299C>T) and heterozygote individuals with massive ectopic calcification (c.1559del and c.1250A>G).
Conclusion: This classification project and the ALPL gene variant database serve the global medical community and widen the genotypic and phenotypic HPP spectrum by classifying ALPL variants based on ACMG/AMP criteria, thus facilitating improved genetic counselling and medical decision-making for affected patients and families and as a repository for clinicians and scientists to query a variant and view evidence of its pathogenicity.
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