Next Generation Sequencing in Intellectual Disability Diagnosis

Background: Intellectual disability (ID) is a neurodevelopmental disorder characterized by deficits in both intellectual and adaptive functioning with onset during the developmental period. Among the known causes for ID, the majority are genetic abnormalities. These conditions are being increasingly diagnosed due to technological advances in genetic testing and the recent availability of next generation sequencing (NGS) techniques has revealed many genes related to ID. Identifying a cause may enable condition-specific intervention, surveillance, and appropriate counselling.

Objective: The objective of this study was to determine the diagnostic yield of whole exome sequencing (WES) based NGS panel in patients with a normal array-based comparative genomic hybridization (aCGH) result.

Methods: We performed a retrospective and descriptive study of children with ID, followed in a neurodevelopment outpatient unit of a level III hospital, to whom a WES based NGS panel that includes 1502 genes ID associated was requested. Data from patients’ clinical files were collected and analysed.

Results: The study included 27 patients; 56% were male. Dysmorphic features were present in 37%. Concerning intelligence quotient (IQ) levels, 41% had an IQ = 56-70, 19% an IQ= 41-55 and 7% an IQ =21-40. Family history of neurodevelopmental disorders was present in 30%. Since aCGH was not able to identify a cause for their ID, all patients performed a WES based NGS panel. NGS identified a likely causative variant in 26% of the children, a possible relevant variant in 52% and variants of uncertain significance in 7%. In 15% no cause was suggested.

Conclusion: NGS techniques represent a major leap forward in the identification of a genetic cause for ID, particularly when aCGH fails to find it.