ABSTRACT
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.