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.