A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases
Authors: Clark Michelle M. , Stark Zornitza , Farnaes Lauge , Tan Tiong Y. , White Susan M. , Dimmock David , Kingsmore Stephen F. 
Published: January 2018

IMPORTANCE

Genetic diseases are a leading cause of childhood mortality. Whole genome sequencing (WGS) and whole exome sequencing (WES) are relatively new methods for diagnosing genetic diseases.

OBJECTIVES

Compare the diagnostic sensitivity (rate of causative, pathogenic or likely pathogenic genotypes in known disease genes) and rate of clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and chromosomal microarrays (CMA) in children with suspected genetic diseases.

DATA SOURCES AND STUDY SELECTION

Systematic review of the literature (January 2011 - August 2017) for studies of diagnostic sensitivity and/or clinical utility of WGS, WES, and/or CMA in children with suspected genetic diseases. 2% of identified studies met selection criteria.

DATA EXTRACTION AND SYNTHESIS

Two investigators extracted data independently following MOOSE/PRISMA guidelines.

MAIN OUTCOMES AND MEASURES

Pooled rates and 95% Cl were estimated with a random-effects model. Metaanalysis of the rate of diagnosis was based on test type, family structure, and site of testing.

RESULTS

In 36 observational series and one randomized control trial, comprising 20,068 children, the diagnostic sensitivity of WGS (0.41, 95% Cl 0.34-0.48, I2=44%) and WES (0.35, 95% Cl 0.31-0.39, I2=85%) were qualitatively greater than CMA (0.10, 95% Cl 0.08-0.12, I2=81%). Subgroup meta-analyses showed that the diagnostic sensitivity of WGS was significantly greater than CMA in studies published in 2017 (P<.0001, I2=13% and I2=40%, respectively), and the diagnostic sensitivity of WES was significantly greater than CMA in studies featuring within-cohort comparisons (P<001, I2=36%). Evidence for a significant difference in the diagnostic sensitivity of WGS and WES was lacking. In studies featuring within-cohort comparisons of singleton and trio WGS/WES, the likelihood of diagnosis was significantly greater for trios (odds ratio 2.04, 95% Cl 1.62-2.56, I2=12%; P<.0001). The diagnostic sensitivity of WGS/WES with hospital-based interpretation (0.41, 95% Cl 0.38-0.45, I2=50%) was qualitatively higher than that of reference laboratories (0.28, 95% Cl 0.24-0.32, I2=81%); this difference was significant in meta-analysis of studies published in 2017 (P=.004, I2=34% and I2=26%, respectively). The rates of clinical utility of WGS (0.27, 95% Cl 0.17-0.40, I2=54%) and WES (0.18, 95% Cl 0.13-0.24, I2-77%) were higher than CMA (0.06, 95% Cl 0.05-0.07, I2=42%); this difference was significant in meta-analysis of WGS vs CMA (P<.0001).

CONCLUSIONS AND RELEVANCE

In children with suspected genetic diseases, the diagnostic sensitivity and rate of clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic sensitivity were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.

Key Points

Question

What is the relative diagnostic sensitivity and clinical utility of different genome tests in children with suspected genetic diseases?

Findings

Whole genome sequencing had greater diagnostic sensitivity and clinical utility than chromosomal microarrays. Testing parent-child trios had greater diagnostic sensitivity than proband singletons. Hospital-based testing had greater diagnostic sensitivity than reference laboratories.

Meaning

Trio genomic sequencing is the most sensitive diagnostic test for children with suspected genetic diseases.