Reanalysis of whole-exome sequencing (WES) data of children with neurodevelopmental disorders in a standard patient care context

Abstract

Abstract Purpose This study aims to inform future genetic reanalysis management by evaluating the yield of whole exome sequencing (WES)-reanalysis in standard patient care in the Netherlands.Methods Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES-analysis and -reanalysis was performed between 1 January 2014 and 31 December 2021 was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis, and if this initial analysis did not result in a diagnosis. Demographic, phenotypic and genotypic characteristics of patients were collected and analyzed. An overview of the technique used, yield and organization of WES-reanalysis in daily care in the 7 genetic departments in the Netherlands was obtained by a questionnaire study. The primary outcomes were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis.Results In most cases, WES-reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients the diagnosis had clinical consequences, as for example a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES-reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001).Conclusions Our results show that WES-reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES-reanalysis, clinical characteristics associated with higher yield and yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists and pediatric neurologists in daily care of patients with NDD.