Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders
In: ISSN: 0340-6717, 2020
academicJournal
Zugriff:
International audience ; Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.
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Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders
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Autor/in / Beteiligte Person: | Tran Mau-Them, Frederic ; Moutton, Sebastien ; Racine, Caroline ; Vitobello, Antonio ; Bruel, Ange-Line ; Nambot, Sophie ; Kushner, Steven ; de Vrij, Femke ; Lehalle, Daphné ; Jean-Marçais, Nolwenn ; Lecoquierre, François ; Delanne, Julian ; Thevenon, Julien ; Poe, Charlotte ; Jouan, Thibaut ; Chevarin, Martin ; Geneviève, David ; Willems, Marjolaine ; Coubes, Christine ; Houcinat, Nada ; Masurel-Paulet, Alice ; Mosca-Boidron, Anne-Laure ; Tisserant, Emilie ; Callier, Patrick ; Sorlin, Arthur ; Duffourd, Yannis ; Faivre, Laurence ; Philippe, Christophe ; Thauvin-Robinet, Christel ; Equipe GAD (LNC - U1231) ; Lipides - Nutrition - Cancer Dijon - U1231 (LNC) ; Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement ; FHU TRANSLAD (CHU de Dijon) ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) ; Erasmus University Medical Center Rotterdam (Erasmus MC) ; Département de génétique médicale, maladies rares et médecine personnalisée CHRU Montpellier ; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier) ; Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB) ; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM) ; Département génétique méd, mal rares et médecine personnalisée CHRU de Montpellier ; Pôle Biologie-Pathologie CHRU Montpellier ; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier) ; Hôpital d'Enfants CHU Dijon ; Hôpital du Bocage ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) |
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Zeitschrift: | ISSN: 0340-6717, 2020 |
Veröffentlichung: | HAL CCSD ; Springer Verlag, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1007/s00439-020-02178-8 |
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