Background: Chromosomal microarray (CMA) is a cytogenetic diagnostic test for chromosomal abnormalities in many diseases, which can provide the fast and accurate detection of copy-number variations (CNVs). International guidelines recommend specific approaches for the use of CMA as a first-tier clinical diagnostic test for patients with developmental disabilities or congenital anomalies. However, CMA is not used as a general diagnostic test in Korea because Korea’s insurance laws do not allow the use of CMA as a clinical diagnostic method. In this study, I aimed to investigate the clinical utility and limitations of CMA as a first-tier chromosome aberration test for patients with developmental delay (DD), intellectual disability (ID), and autism spectrum disorders (ASD) in Korea.
Methods: Eighty-seven patients with neurodevelopmental disorders (16 ID, 70 DD and one ASD) and 32 patients with both congenital anomalies and symptoms of ID or DD revealed normal conventional G-banded karyotypes and were therefore referred by a clinical geneticist for further chromosomal analysis from December 2012 to July 2016. CMA was performed in a single clinical laboratory on a total of 182 samples from 119 patients and 63 family members of 37 patients. The clinical significance of CNVs and clinical features of patients and family members were studied.
Results: The CMA results of 119 patients revealed 36 pathogenic CNVs (30.3%), 11 CNVs of variants of uncertain clinical significance (VOUS) (7.6%), 24 benign CNVs (17.6%), and no abnormalities in 53 patients (44.5%). Among the 63 family members of 37 patients, the CMA results revealed five pathogenic CNVs (8%), five VOUS (8%), 12 benign CNVs (19%), and no abnormalities in 41 cases (65%). In the 11 family members with abnormal phenotypes, the CMA results revealed five pathogenic CNVs (45.5%), two VOUS (18.2%), one benign CNV (9.1%), and three normal results (27.3%). The detection rate for pathogenic CNVs was 30.3% (36/119), which is higher than the average detection rate of previous reports.
Conclusions: In this study, pathogenic CNVs were detected in 36 patients (30.3%) and it was demonstrated that CMA is a very powerful tool with clinical diagnostic utility for patients with DD, ID, ASD, and congenital anomalies. However, there was a limitation of CMA results with VOUS for interpretation for nine patients (7.6%). The significance of VOUS can be improved by further testing through a familial studies and exome sequencing.
