Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis.

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Date publication

novembre 2017


Genetics in medicine : official journal of the American College of Medical Genetics


Membres identifiés du Cancéropôle Est :
Pr CALLIER Patrick, Pr FAIVRE Laurence, Pr VABRES Pierre, Dr NAMBOT Sophie

Tous les auteurs :
Nambot S, Thevenon J, Kuentz P, Duffourd Y, Tisserant E, Bruel AL, Mosca-Boidron AL, Masurel-Paulet A, Lehalle D, Jean-Marçais N, Lefebvre M, Vabres P, El Chehadeh-Djebbar S, Philippe C, Tran Mau-Them F, St-Onge J, Jouan T, Chevarin M, Poé C, Carmignac V, Vitobello A, Callier P, Rivière JB, Faivre L, Thauvin-Robinet C,


PurposeCongenital anomalies and intellectual disability (CA/ID) are a major diagnostic challenge in medical genetics-50% of patients still have no molecular diagnosis after a long and stressful diagnostic "odyssey." Solo clinical whole-exome sequencing (WES) was applied in our genetics center to improve diagnosis in patients with CA/ID.MethodsThis retrospective study examined 416 consecutive tests performed over 3 years to demonstrate the effectiveness of periodically reanalyzing WES data. The raw data from each nonpositive test was reanalyzed at 12 months with the most recent pipeline and in the light of new data in the literature. The results of the reanalysis for patients enrolled in the third year are not yet available.ResultsOf the 416 patients included, data for 156 without a diagnosis were reanalyzed. We obtained 24 (15.4%) additional diagnoses: 12 through the usual diagnostic process (7 new publications, 4 initially misclassified, and 1 copy-number variant), and 12 through translational research by international data sharing. The final yield of positive results was 27.9% through a strict diagnostic approach, and 2.9% through an additional research strategy.ConclusionThis article highlights the effectiveness of periodically combining diagnostic reinterpretation of clinical WES data with translational research involving data sharing for candidate genes.GENETICS in MEDICINE advance online publication, 2 November 2017. doi:10.1038/gim.2017.162.

Mots clés

Congenital Abnormalities, genetics, Databases, Genetic, Exome, Genetic Testing, methods, High-Throughput Nucleotide Sequencing, methods, Humans, Intellectual Disability, genetics, Rare Diseases, genetics, Retrospective Studies, Sequence Analysis, DNA, methods, Whole Exome Sequencing, methods


Genet. Med.. 2017 Nov 2;: