Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability A systematic review and meta-analysis

Abstract Importance: Clinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Several reviews have been published regarding clinical genetic testing in various NDD subtypes. However, there is no systematic review and meta-analysis – in accordance with the PRISMA guidelines – which compares the genetic testing yield across neurodevelopmental disorder subtypes and sequencing technology. Objective: To perform a meta-analysis and systematic review of the success rate (diagnostic yield) of clinical sequencing through NGS across NDDs. Data Sources: Systematic review of the literature from PubMed until July 2019 for clinical sequencing studies that utilized NGS in individuals with epilepsy, autism spectrum disorder (ASD), or intellectual disability (ID). Study Selection: Data were taken from clinical sequencing studies that screened more than five genes and performed variant classification in at least 20 individuals with epilepsy, ASD, or ID. 5.6% of identified studies met the selection criteria. Data Extraction and Synthesis: Data were extracted, reviewed, and categorized according to PRISMA guidelines. Clinical evaluation and grouping were performed by two investigators following the ILAE guidelines. Pooled rates of the diagnostic yield and 95% confidence intervals were estimated with a random-effects model and adjusted for publication bias by the Duval and Tweedie procedure. Main Outcomes and Measures: Diagnostic yield, defined as the proportion of individuals in a cohort who received a diagnosis based on a positive genetic test with variants identified as pathogenic or likely pathogenic. Results: We identified 79 studies (epilepsy, n = 54; ASD, n = 13; ID, n = 17) across 29,301 individuals. Targeted gene panel sequencing was used in 53 cohorts and exome sequencing (ES) in 27 cohorts. The diagnostic yield was 16.7% for epilepsy, 20.2% for ASD, 24.8% for ID, and 16.6% overall. The diagnostic yield was significantly higher for exome sequencing compared to panels (33.9% vs. 16.2%, P = 1.38×10−5). We observed that the number of clinical sequencing studies increased annually, particularly studies from Asia (0-2 per year between 2012 and 2017, up to 10 in 2018). No studies from Africa, India, or Latin America were identified. We also found that recent studies are more likely to report variants of uncertain significance and few studies reported benign variants. Conclusions and Relevance: This meta-analysis and systematic review provides a comprehensive overview of clinical sequencing studies of NDDs, which will help guide policymaking and steer decision-making in patient management. Key Points Question What is the diagnostic yield of next-generation sequencing (NGS) in neurodevelopmental disorders and their subtypes? Findings In this systematic review and meta-analysis of 79 studies that include 29,301 individuals, the overall diagnostic yield was 16.6% (16.7% for epilepsy, 20.2% for ASD, and 24.8% for ID). Across all studies, downstream analyses showed a significant difference in yield between exome sequencing (33.9%) and targeted gene panels (16.2%). Meaning Around one in five NDD patients will receive a diagnosis using NGS, especially when investigating the whole exome.