In 2010, chromosomal microarray was recommended by the American College of Medical Genetics and Genomics as the first-line genetic test for identifying chromosomal copy number variations [2], with a diagnostic rate of approximately 10% to 25% [3]. However, recent advancements in molecular cytogenetics, particularly next-generation sequencing-based technologies, have significantly improved diagnostic yields. These include targeted gene panel sequencing, exome sequencing with copy number variation analysis, and whole-genome sequencing (WGS). Whole-exome sequencing (WES) enables precise identification of exon-level single-nucleotide variants and small insertions or deletions through massively parallel DNA sequencing. This approach is particularly valuable in cases where differential diagnosis is challenging due to heterogeneous phenotypic presentations, or when targeted gene panels or chromosomal microarrays fail to yield a conclusive diagnosis. Therefore, WES is increasingly recognized as a first-tier diagnostic tool for rare and undiagnosed Mendelian disorders [4].

In accordance with the updated 2021 guidelines from the American College of Medical Genetics and Genomics, WES and WGS are now recommended as first- or second-tier diagnostic tests for patients with GDD or ID, effectively supplanting chromosomal microarray as the preferred first-tier test [2]. This paradigm shift is driven by accumulating evidence underscoring the superior diagnostic yield of next-generation sequencing-based methodologies. Notably, WES has demonstrated a diagnostic yield of 48.8% in Korean children with DD/ID [3], while a 2021 Japanese study reported pathogenic variant identification in 53.5% of DD/ID cases [5].

Kim et al. [6] reported a case of a child with GDD who underwent extensive diagnostic evaluation, initially starting with chromosomal microarray but ultimately receiving a definitive diagnosis of Radio-Tartaglia syndrome through WGS in our journal. The study further compared the clinical phenotypic characteristics of this case with those observed in patients with 1p36 deletion syndrome, highlighting the diagnostic utility of WGS in differentiating genetically heterogeneous conditions [6].

WES and WGS are both powerful genetic diagnostic tools, but they differ in scope and clinical utility. WES focuses on protein-coding regions, which harbor the majority of known pathogenic variants, making it a cost-effective and widely used first-line test for genetic disorders. In contrast, WGS provides a more comprehensive analysis by covering both coding and non-coding regions, enabling the detection of structural variants, deep intronic mutations, and regulatory region alterations that WES may miss. Although WGS offers a higher diagnostic yield and broader variant detection capabilities, its higher cost and increased data complexity currently limit its routine use as a first-tier test. Therefore, WES remains the preferred initial approach, with WGS reserved for cases where WES fails to identify a genetic cause. Ko and Chen [7] analyzed previous studies and reported that WGS has a diagnostic yield ranging from 21% to 63%, while WES typically yields between 21% and 66%. However, as the number of WGS-based studies remains relatively limited, further comparative data are needed to draw more definitive conclusions.

In conclusion, timely and precise diagnostic evaluations are crucial for elucidating the underlying etiologies of DD in children. Rather than prolonging the diagnostic odyssey, early implementation of targeted genetic assessments facilitates optimal therapeutic interventions, improves neurodevelopmental outcomes, alleviates parental distress, and promotes a more structured and effective approach to patient management.