Genome sequencing(GS) has been applied in the diagnosis of global
developmental delay(GDD)/intellectual disability(ID). However, the
performance in those 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 prior to enrollment. Reanalysis of
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 23%. Seven families could have been solved
with reanalysis of ES data. 13 families were missed by previous CMA/ES
due to improper method. Three remained unsolved after ES reanalysis due
to allele dropout, 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 cohort of undiagnosed
GDD/ID patients, detecting a wide range of variant types of different
sizes in a single workflow.
Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders
