Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study

Abstract

Genome sequencing (GS) has been used in the diagnosis of global developmental delay (GDD)/intellectual disability (ID). However, the performance of GS in patients with inconclusive results from chromosomal microarray analysis (CMA) and exome sequencing (ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test before enrollment. Reanalysis of their CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 21%. Seven cases could have been solved with reanalysis of ES data. Thirteen families were missed by previous CMA/ES due to improper methodology. Two remained unsolved after ES reanalysis due to complex variants missed by ES, and a CNV in untranslated regions. Follow‐up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this undiagnosed GDD/ID cohort, detecting a wide range of variant types of different sizes in a single workflow.

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

“…ES is unable to cover all the exomes and is prone to having false negative gaps in GC-rich regions, repetitive regions, regions with pseudogenes, and regions with high homology [ 80 ]. Additionally, low probe affinity for the highly variable regions and missed coverage could both lead to false negative results [ 7 ]. The regions with reduced coverage depend on sequencing metrics and may differ between labs.…”

“…GS has the potential to become the first-tier etiologic evaluation of GDD/ID, especially in identifying short segment variants missed by CMA, and CNV and non-coding segment deletions or allele dropouts missed by ES [ 7 ]. The challenge in GS is the variant prioritization and interpretation of these complex, rare, and non-coding region variants.…”

“…Recently, high-throughput sequencing, such as ES or GS, has allowed for rapid, in-depth analysis of the human genome. New evidence is showing support for MPS to replace CMA as the first-tier test for unexplained autistic spectrum disorder, GDD/ID, and MCA [ 6 , 7 , 8 , 9 ]. ACMG has also published an updated guideline to recommend ES and GS as the first-tier genetic evaluation for patients with ID [ 10 ].…”

Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability

“…Genome sequencing (GS) is an NGS approach that determines the sequence of most of the DNA of the entire genome of an individual. The main advantage of GS over ES is the ability to query intronic regions, and its superior ability compared with ES to detect structural rearrangements including small and large CNVs [ 43 , 65 ]. GS is not yet clinically available in most centers, and its use is still mainly restricted to research paradigms.…”

“…GS is not yet clinically available in most centers, and its use is still mainly restricted to research paradigms. One study demonstrated that the addition of GS to the investigation of patients with GDD/ID following unrevealing initial testing (either CMA, ES or both) had a diagnostic yield of 21% [ 65 ]. The yield was 64% if only a CMA had been previously performed and 14% if ES was performed [ 65 ].…”