New generation sequencing for the diagnosis of intellectual disabilities: Exome sequencing or large panel?

Abstract

Objective: Clinical and genetic heterogeneity in intellectual disability (ID) represent a major challenge for etiological diagnosis, since more than 600 genes are involved in ID. A genetic diagnosis can provide information on prognosis, potential treatment options and genetic counseling. Next Generation Sequencing (NGS) greatly improved the diagnosis yield in ID, up to 40%. Our objective was to evaluate successively two NGS strategies as the last-tier test for the diagnosis process in patients with ID referred to our genetic unit: large gene panel and whole exome sequencing (WES). Methods: We included 368 patients with ID referred to our genetic unit, after clinical evaluation and negative testing, i.e array CGH, Fragile X testing and targeted gene sequencing (when done). We performed trio based NGS (parents + affected proband) using TruSightTOne (TS1) genes panel (including 4813 OMIM referred genes) for the first 263 patients, and then exome sequencing (WES) for the next 127 patients with ID. 22 patients were studied with both tools. Results: Our diagnosis rate was 21% with TS1 and 42% with WES. More than half of the disease-causing mutations identified with WES were found in genes not included in TS1, because they were too recently described (29/53 = 55%). Seven diagnoses with WES were performed in 22 patients with no diagnosis with TS1 (32%). Moreover, 9 additional likely pathogenic variants were found with WES in yet unpublished genes (ongoing international collaborations). All diagnoses were validated thanks to a strong collaboration between clinical and biological geneticists. Conclusion: NGS is a powerful tool for etiological diagnosis in ID. WES has a better diagnostic yield than a large panel because of the rapid advancement of knowledge and the regular identification of new genes of intellectual disability. A clinical validation of the sequenced variants is an indispensable step in the diagnosis process.