Clinical sequencing yield in epilepsy, autism spectrum disorder, and
intellectual disability A systematic review and meta-analysis
Authors: Stefanski Arthur , Calle-López Yamile , Leu Costin , Pérez-Palma Eduardo , Pestana-Knight Elia , Lal Dennis 
Published: May 2020

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.