Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

Julien Thevenon; Yannis Duffourd; Alice Masurel-Paulet; M. Lefebvre; François Feillet; S. El Chehadeh-Djebbar; Judith Saint-Onge; A. Steinmetz; Frédéric Huet; M. Chouchane; V. Darmency-Stamboul; Patrick Callier; Christel Thauvin-Robinet; Laurence Faivre; Jean-Baptiste Rivière

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

Julien Thevenon ^{1, 2} Yannis Duffourd ² Alice Masurel-Paulet ^{2, 1} M. Lefebvre ^{2, 1} François Feillet ^{3, 4} S. El Chehadeh-Djebbar ⁵ Judith Saint-Onge ^{1, 2} A. Steinmetz ^{2, 1} Frédéric Huet ⁶ M. Chouchane ⁶ V. Darmency-Stamboul ⁶ Patrick Callier ^{1, 2, 7} Christel Thauvin-Robinet ^{1, 2} Laurence Faivre ^{2, 1} Jean-Baptiste Rivière ^{2, 1, 7}

1 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)

2 GAD - Génétique des Anomalies du Développement

3 MaMEA Nancy-Brabois - Centre de référence des maladies héréditaires du métabolisme

4 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux

5 Hôpital de Hautepierre [Strasbourg]

6 Service de pédiatrie (CHU de Dijon)

7 Laboratoire de Génétique Chromosomique et Moléculaire

Abstract : The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ~50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.

Keywords : Intelectual disability : encephalopathy

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Médecine humaine et pathologie

Liste complète des métadonnées

https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01405124
Contributeur : Gad - Université de Bourgogne <>
Soumis le : mardi 29 novembre 2016 - 15:28:01
Dernière modification le : vendredi 8 juin 2018 - 14:50:18

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

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Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

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