Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Abstract

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

• Authors: Agnès Taillandier, Christelle Domingues, Clémence De Cazanove, Valérie Porquet-Bordes, Sophie Monnot, Tina Kiffer-Moreira, Agnès Rothenbuhler, Pascal Guggenbuhl, Catherine Cormier, Geneviève Baujat, Françoise Debiais, Yline Capri, Martine Cohen-Solal, Philippe Parent, Jean Chiesa, Anne Dieux, Florence Petit, Joelle Roume, Monica Isnard, Valérie Cormier-Daire, Agnès Linglart, José Luis Millán, Jean-Pierre Salles, Christine Muti, Brigitte Simon-Bouy, Etienne Mornet
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 116 Issue 3 Pg. 215-20 (Nov 2015) ISSN: 1096-7206 [Electronic] United States
• PMID: 26432670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Topics

• Adult
• Aged
• Campomelic Dysplasia (diagnosis)
• Child, Preschool
• Diagnosis, Differential
• Female
• Fetus
• High-Throughput Nucleotide Sequencing
• Humans
• Hypophosphatasia (diagnosis, genetics, physiopathology)
• Infant
• Male
• Middle Aged
• Mutation
• Oligonucleotide Array Sequence Analysis
• Osteogenesis Imperfecta (diagnosis)
• Tooth Demineralization (congenital, physiopathology)