Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

Abstract

Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene–disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID.

Diagnostic findings and yield of investigations for children with developmental regression

“…The diagnostic yield of ES in developmentally delayed children has been reported to be higher than CMA alone, with yields of 36%–53% reported (Srivastava et al, 2022). Higher diagnostic yields are reported for neurodevelopmental conditions with additional features (Ko & Chen, 2023) or for children who have consanguineous parents (Masri et al, 2023). We report 29 pathological genetic variants based on the American College of Medical Genetics five tier criteria (Richards et al, 2015).…”

Comprehensive evaluation of the child with global developmental delays or intellectual disability

“…Furthermore, it is the most effective A c c e p t e d A r t i c l e diagnostic tool for evaluating GDD/ID after a thorough history and comprehensive physical examination. [46][47][48] In one study, a chromosome microarray analysis (CMA) was performed in patients with normal karyotype results, resulting in a diagnostic yield of 21.7% (18 of 83). 30) Two CMA platforms were used to analyze chromosome array comparative genomic hybridization and single-nucleotide variant arrays.…”

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders

“…The use of targeted panel whole exome sequencing (WES), whole genome sequencing (WGS), and increasingly, RNA sequencing (RNASeq) combined with WGS, have become the standard for identifying rare genetic developmental disabilities [1][2][3][4][5]. Even with these advances, as many as half of unexplained cases of developmental disability have no known genetic cause [6].…”

“…However, this represents a significant improvement from 2010 [7], when the first gene for Mabry syndrome (HPMRS1 or GPIBD2; MIM 239300) was identified by Krawitz et al [8]. The subsequent advances in genomic diagnostics have had a profound impact on clinical genetics [1][2][3][4][5] and genomic counselling [9]. By these means, novel disease pathways have been identified, including the Glycophosphatidylinositol (GPI) biosynthesis pathway that is disrupted in at least 21 developmental disabilities [10].…”