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

Abstract

Objective: Clinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Here we perform a meta-analysis and systematic review of the success rate (diagnostic yield) of clinical sequencing through next-generation sequencing (NGS) across NDDs. We compare the genetic testing yield across NDD subtypes and sequencing technology.

Methods: We performed a systematic review of the PubMed literature until May 2020. We included clinical sequencing studies that utilized NGS in individuals with epilepsy, autism spectrum disorder (ASD), or intellectual disability (ID). Data were extracted, reviewed, and categorized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators performed clinical evaluation and grouping following the International League Against Epilepsy (ILAE) guidelines. Pooled rates of the diagnostic yield and 95% confidence intervals were estimated with a random-effects model.

Results: We identified 103 studies (epilepsy, N = 72; ASD, N = 14; ID, N = 21) across 32,331 individuals. Targeted gene panel sequencing was used in 73, and exome sequencing in 36 cohorts. Given highly selected patient cohorts, the diagnostic yield was 17.1% for ASD, 24% for epilepsy, and 28.2% for ID (23.7% overall). The highest diagnostic yield for epilepsy subtypes was observed in individuals with ID (27.9%) and early onset seizures (36.8%). The diagnostic yield for exome sequencing was higher than for panel sequencing, even though not statistically significant (27.2% vs 22.6%, P = .071). We observed that clinical sequencing studies are performed predominantly in countries with a high Inequality-adjusted Human Development Index (IHDI) (countries with sequencing studies: IHDI median = 0.84, interquartile range [IQR] = 0.09 vs countries without sequencing studies: IHDI median = 0.56, IQR = 0.3). No studies from Africa, India, or Latin America were identified, indicating potential barriers to genetic testing.

Significance: This meta-analysis and systematic review provides a comprehensive overview of clinical sequencing studies of NDDs and will help guide policymaking and steer decision-making in patient management.

Keywords: autism; epilepsy; genetics; neurodevelopmental disorders; sequencing.

Figure 1

Process of data search, identification, and filtering

Figure 2

Separation of 103 unique studies included. We collected 103 studies which included heterogeneous types of NDDs. We were able to separate these into 107 distinct disorder cohorts, 81 cohorts by seizure type, 41 DEE cohorts, 21 cohorts by age at onset, and 109 sequencing technology cohorts. Abbreviations: ASD, autism spectrum disorder; DD, developmental delay; DEE, developmental epileptic encephalopathy; ES, exome sequencing; FE, focal epilepsy; GE & FE, combined generalized and focal epilepsy; GE, generalized epilepsy; ID, intellectual disability; panel, targeted gene panel sequencing; WS, West syndrome

Figure 3

Forest plot of meta‐analysis of the overall diagnostic yield from 103 studies. Abbreviations: CI, confidence interval; I2, estimated proportion of the variance in study estimates that is due to heterogeneity; Proportion, fraction of individuals with a positive genetic test (ie, pathogenic or likely pathogenic variant)

Figure 4

Diagnostic yield by sequencing technology. The mean yield in ES is higher compared to panel testing, even though the difference is not statistically significant‐ 27.2% vs 22.6% (P = .071). Abbreviations: ES, exome sequencing; panel, targeted gene panel sequencing

Figure 5

Inequality‐adjusted Human Development Index (IHDI) by country group. Countries with sequencing studies have a significantly higher median Inequality‐adjusted Human Development Index (IHDI), compared to countries without sequencing studies 0.84 vs 0.56 (P = 5.8 × 10‐11)