Next-generation sequencing (NGS) is a powerful tool to improve diagnostic yield in intellectual disability

Abstract

Objective: While Intellectual Disability (ID) affects about 1.5 to 2% of children, many patients still have no etiological diagnosis. In recent years, Next-Generation Sequencing has permitted the discovery of many new genes increasing genetic heterogeneity of intellectual disability and now allows rapid testing of a large number of genes. Methods: We report our 18-months experience with a 450-gene panel. Sequencing was performed on a Nextseq500 (Illumina®) after SureSelectXT capture (Agilent). Results: Over the 212 patients tested, 114 results have already been returned to the clinician. Disease-causing variants were found in ACTB, ADNP (2), ARID1B, CHD2, CUX2, DCX, EHMT1, FOXG1, GATAD2B, GRIN2B, HIVEP2, IL1RAPL1, IQSEC2 (4), KANSL1, KIAA2022, KMT2D (3), MECP2, NFIX, NSD1, PACS1, PCDH19, PDHA1, POGZ, RPS6KA3, SATB2 (2), SCN2A (2), SETBP1, SETD5 (2), SHANK3, SLC2A1, SMS, SYNGAP1 (3), TCF4, UBE3A for a total of 45 diagnosis. Five missense variants of unknown significance were also found, all located on the X chromosome (ARX, CASK, GRIA3, IQSEC2, and PTCHD1) and all inherited from a non-affected mother. This highlights the difficulty of pathogenicity assessment for missense variants of the X-chromosome, in lack of multiple affected individuals. No incidental finding was discovered stressing a clear advantage of this panel strategy versus whole-exome/genome sequencing. Conclusion: Whereas only a handful genes were accessible until recently (too many genes to sequence, too expensive, time consuming), our panel approach currently reaches a diagnostic yield of 21% in a reasonable turnaround time. Considering ongoing discoveries the diagnostic yield will probably increase while moving to whole-exome or whole-genome sequencing. These approaches will also enable “reverse phenotyping”: better phenotypic description and possible phenotypic spectrum broadening, preliminary to therapeutic opportunities.