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

Nambot S1,2,3,4, Thevenon J1,3,4, Kuentz P2,3,4, Duffourd Y3,4, Tisserant E3,4, Bruel AL3,4, Mosca-Boidron AL2,3,4, Masurel-Paulet A1,3, Lehalle D1, Jean-Marçais N1,3, Lefebvre M1,2, Vabres P3,4, El Chehadeh-Djebbar S1, Philippe C2,4, Tran Mau-Them F2,4, St-Onge J2,4, Jouan T2,3,4, Chevarin M2,3,4, Poé C2,3,4, Carmignac V4, Vitobello A2,3,4, Callier P2,3,4, Rivière JB2,3,4, Faivre L1,3,4, Thauvin-Robinet C1,2,3,4; Orphanomix Physicians' Group.

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Abstract

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.