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Mol Genet Metab. 2015 Nov;116(3):215-20. doi: 10.1016/j.ymgme.2015.09.010. Epub 2015 Sep 30.

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

Author information

1
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: ataillandier@ch-versailles.fr.
2
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: christelle.adam1@voila.fr.
3
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: c.de.casanove@outlook.fr.
4
Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU de Toulouse, Toulouse Cedex 9, France. Electronic address: porquet-bordes.v@chu-toulouse.fr.
5
Université Paris-Descartes, Sorbonne Paris Cité, Institut Imagine and INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: sophie.monnot@nck.aphp.fr.
6
Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: kiffer-moreira@sanfordburnham.org.
7
APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, Le Kremlin Bicêtre 94270, France; APHP, Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme D'expertise Paris Sud, Le Kremlin Bicêtre 94270, France. Electronic address: anya.rothenbuhler@bct.aphp.fr.
8
Service de Rhumatologie, Hôpital Sud, CHU de Rennes, 16, Boulevard de Bulgarie, BP90347, 35203 Rennes Cedex 2, France. Electronic address: pascal.guggenbuhl@chu-rennes.fr.
9
Rheumatology Department, Cochin University Hospital, 75015 Paris, France. Electronic address: Catherine.Cormier@cch.ap-hop-paris.fr.
10
Centres de Référence Maladies Osseuses Constitutionnelles (MOC), Hôpital Universitaire Necker-Enfants Malades et Institut Imagine (AP-HP), 75015 Paris, France. Electronic address: genevieve.baujat@nck.aphp.fr.
11
Service de rhumatologie, CHU de Poitiers, 86021 Poitiers Cedex, France. Electronic address: francoise.debiais@chu-poitiers.fr.
12
Department of Genetics, APHP-Robert Debré University Hospital, Paris, France. Electronic address: yline.capri@aphp.fr.
13
Department of Rheumatology, INSERM UMR-1132, Lariboisière Hospital and University, Paris Diderot Sorbonne, Paris, France. Electronic address: martine.cohen-solal@inserm.fr.
14
Service de Génétique Clinique, CHU Brest, Brest F-29200, France. Electronic address: philippe.parent@chu-brest.fr.
15
Department of Genetics, University Hospital, Nîmes, France. Electronic address: jean.chiesa@chu-nimes.fr.
16
Service de Génétique Clinique, CHU, Lille, France. Electronic address: anne.dieux@chru-lille.fr.
17
Service de Génétique Clinique, CHU, Lille, France. Electronic address: florence.petit@chru-lille.fr.
18
Unité de Génétique Médicale, Centre Intercommunal Poissy-St-Germain en Laye, Poissy, France. Electronic address: drjroume@gmail.com.
19
Gynécologie Obstétrique, Centre Hospitalier de Mulhouse, 68051 Mulhouse Cedex, France.
20
Université Paris-Descartes, Sorbonne Paris Cité, Institut Imagine and INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: valerie.cormier-daire@inserm.fr.
21
APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, Le Kremlin Bicêtre 94270, France; APHP, Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme D'expertise Paris Sud, Le Kremlin Bicêtre 94270, France. Electronic address: agnes.linglart@aphp.fr.
22
Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: millan@sanfordburnham.org.
23
Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU de Toulouse, Toulouse Cedex 9, France. Electronic address: salles.jp@chu-toulouse.fr.
24
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: cmuti@ch-versailles.fr.
25
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: bsimon-bouy@ch-versailles.fr.
26
Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, 78150 Le Chesnay, France. Electronic address: emornet@ch-versailles.fr.

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.

KEYWORDS:

Differential diagnosis; Hypophosphatasia; NGS; Osteogenesis imperfecta

PMID:
26432670
PMCID:
PMC5257278
DOI:
10.1016/j.ymgme.2015.09.010
[Indexed for MEDLINE]
Free PMC Article

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