Chromosomal Microarray Analysis as a First-Tier Clinical Diagnostic Test in Patients With Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies: A Prospective Multicenter Study in Korea

Abstract

Background: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA).

Methods: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results.

Results: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively.

Conclusions: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.

Keywords: Autism spectrum disorders; Benign; Chromosomal microarray analysis; Clinical management; Developmental delay; Intellectual disability; Multiple congenital anomalies; Pathogenic; Variant of possible significance; Variant of unknown significance.

Fig. 1. Evaluation of clinical features in patients with DD/ID, ASD, and MCA. Significant differences in the frequencies of ID, dysmorphic features, and hypotonia were found among the three groups (P=0.029, P<0.001, and P=0.006, respectively).

^*P<0.05; ^**P<0.001. Abbreviations: DD, developmental delay; ID, intellectual disability; ASD, autism spectrum disorders; MCA, multiple congenital anomalies; VUS, variants of unknown significance.

Fig. 2. Rate of clinical management recommendations following CMA.

^*P<0.05; ^**P<0.001. Abbreviations: CMA, chromosomal microarray analysis; VUS, variants of unknown significance; CT, computed tomography; MRI, magnetic resonance imaging.