Genetic tests by next-generation sequencing in children with developmental delay and/or intellectual disability

Abstract

Developments in next-generation sequencing (NGS) techogies have assisted in clarifying the diagnosis and treatment of developmental delay/intellectual disability (DD/ID) via molecular genetic testing. Advances in DNA sequencing technology have not only allowed the evolution of targeted panels but also, and more currently enabled genome-wide analyses to progress from research era to clinical practice. Broad acceptance of accuracy- guided targeted gene panel, whole-exome sequencing (WES), and whole-genome sequencing (WGS) for DD/ID need prospective analyses of the increasing cost-effectiveness versus conventional genetic testing. Choosing the appropriate sequencing method requires individual planning. Data are required to guide best-practice recommendations for genomic testing, regarding various clinical phenotypes in an etiologic approach. Targeted panel testing may be recommended as a first-tier testing approach for children with DD/ID. Family-based trio testing by WES/WGS can be used as a second test for DD/ ID in undiagnosed children who previously tested negative on a targeted panel. The role of NGS in molecular diagnostics, treatment, prediction of prognosis will continue to increase further in the coming years. Given the rapid pace of changes in the past 10 years, all medical providers should be aware of the changes in the transformative genetics field.

Comorbidities associated with genetic abnormalities in children with intellectual disability

“…However, the etiology of DD/ID is very extensive and diverse 2 – 4 . Thus, to identify an etiology in DD/ID children is a challenge to clinicians, particularly in those who failed to obtain a diagnosis despite using the suggested stepwise systemic clinical evaluations 10 , 12 , 14 . The rapid development of NGS technology makes molecular genetic tests available in clinical practice, but its cost may not be affordable for most families.…”

Detection of Disease-Causing SNVs/Indels and CNVs in Single Test Based on Whole Exome Sequencing: A Retrospective Case Study in Epileptic Encephalopathies

“…Among them, aCGH has been proven as an indispensable approach to screen CNVs associated with epilepsy, intellectual disability, developmental delay, or congenital anomalies in children ( 45 ). In the past decade, WES, which refers to sequencing of all protein-coding exons, has been widely used in genetic testing in Mendelian disorders as well as other complex diseases ( 46 ). It is powerful to detect SNVs/Indels in enriched protein-coding regions.…”

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

“…Over 6500 phenotypes were included in the OMIM by the end of 2019 and most of them were onset during childhood. Genetic pediatric disorders are highly heterogeneous and relatively rare, which, for investigating them, necessitates a process of serial testing for specific conditions (Han and Lee, 2020). In consequence, this strategy may be expensive and timeconsuming.…”

“…Generally, these genomic tests include whole exome sequencing (WES) and chromosomal microarray analysis (CMA). WES has been ordered increasingly in clinical molecular diagnosis laboratories as a powerful tool for rare Mendelian disorders, especially for genetically heterogeneous disorders such as intellectual developmental disorders and multiple congenital anomalies (Bowling et al, 2017;Han and Lee, 2020). According to previous researches, the overall diagnostic yields among different cohorts were ∼25% (Yang et al, 2013(Yang et al, , 2014Lee et al, 2014).…”