1 INTRODUCTION
Intellectual disability (ID), a condition characterized by significant
limitations in general mental abilities and adaptive functioning that
emerge during child development, is one of the most frequently reported
impairments in children(Robert L.
Schalock, 2021). The overall prevalence is around
1%(McGuire, Tian, Yeargin-Allsopp,
Dowling, & Christensen, 2019). For younger patients in whom IQ scores
are difficult to obtain, global developmental delay (GDD) is a condition
assigned to patients who show significant delays in two or more
developmental domains: fine/gross motor skills, speech/language,
social/personal skills and daily living
(Choo, Agarwal, How, & Yeleswarapu,
2019).
Early evaluation of children with suspected GDD/ID is valuable in
determining whether intervention is required. Due to the high genotypic
heterogeneity of GDD/ID, genomic diagnostic tests, such as chromosomal
microarray analysis (CMA) and exome sequencing (ES) are frequently
recommended to obtain a molecular genetic diagnosis. CMA focuses on copy
number variations (CNV), and is recommended as the first-tier method to
diagnose ID or GDD by many
associations(Miller et al., 2010;
Subspecialty Group of Neurology & Project
Expert Group of Childhood Neuropathy, 2018). The diagnostic yield of
CMA in this population ranges from
12-20%(Miller et al., 2010;
Moeschler, Shevell, & Committee on,
2014). Exome sequencing (ES) was initially used to detect small
variants in regions of interest (ROI). A recent meta-analysis revealed
that ES helped to solve 36% (range 8-90%) of cases in patients with
suspected neurodevelopmental disorders (NDD), and has been recommended
as a first-tier clinical diagnostic test for
NDD(Srivastava et al., 2019). Periodic
reanalysis of ES data can also provide additional diagnoses as new
gene-disease associations are reported
(Wenger, Guturu, Bernstein, & Bejerano,
2017; Xiao et al., 2018), and new
algorithms are developed that enable variant calling beyond that of
small variants(Fan et al., 2021;
Sun et al., 2020).
Despite these recommendations, an important question remains: What is
recommended for patients who remain undiagnosed after CMA, ES, or ES
reanalysis? Studies have shown that many pathogenic variants are located
outside of protein-coding regions of the genome which are not covered
with ES or CMA. Genome sequencing (GS) can detect virtually all types of
variation (e.g., chromosomal structural variation, trinucleotide
repeats, mitochondrial variants) in the human genome without probe
selection bias (Meynert, Ansari,
FitzPatrick, & Taylor, 2014; Pang,
Macdonald, Yuen, Hayes, & Scherer, 2014) and has been applied to
clinical practice(French et al., 2019;
Marshall et al., 2020;
Wright, FitzPatrick, & Firth, 2018). For
example, when used in the neonatal intensive care unit (NICU) setting,
rapid GS demonstrates ultra-fast turn-around time, decreased rates of
infant morbidity and reduced cost of
hospitalization(Farnaes et al., 2018).
Thus, adoption of GS has the potential to reduce or eliminate the
diagnostic odyssey in patients with GDD/ID and have downstream effects
on care management(Bowling et al., 2017;
Gilissen et al., 2014;
Zahir et al., 2017). Moreover, with the
drop in sequencing price and development of data processing tools, GS
could be offered as the first-tier test for select indications such as
GDD/ID(Lindstrand et al., 2019;
Lionel et al., 2018). Even only a small
number of clinics would perform GS as the first test of choice
currently. The American College of Medical Genetics and Genomics (ACMG)
recommended GS as a first-tier or second-tier test for pediatric
patients with congenital anomalies or ID together with ES in a recently
published clinical guideline(Manickam et
al., 2021).
Here, we present the results of
a
multi-center prospective study that evaluated the diagnostic and
clinical utility of GS in children with suspected GDD/ID.