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.

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

“…2,3 More recent studies on cohorts of patients with CA/ DD/ID have documented diagnostic yields ranging from 16% to 28%. [4][5][6] As a result, CMA is a well-established tool in clinical practice, yet this testing will not capture singlenucleotide variations (SNVs) or small insertion/deletions (indels), smaller structural variants, and other pathogenic variant types contributing to CA/DD/ID.…”

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

“…SNP array can detect not only CNVs, but also uniparental disomy and chimera. CMA has the advantage of high throughput and high resolution, and has been proven to be a powerful diagnostic tool in cases with developmental delays/mental retardation, autism syndrome, multiple birth defects, etc 2 – 4 . With the wide application of CMA as a prenatal diagnostic technique, clinical values of chromosomal microdeletions and microduplications are increasingly recognized.…”

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

“…Previous WES studies revealed a diagnosis rate of ∼25-30% in nonselective patients (Yang et al, 2013(Yang et al, , 2014Lee et al, 2014;Daoud et al, 2016;Retterer et al, 2016). Moreover, additional pathogenic and likely pathogenic CNVs were also identified in over 10% of patients (Sanmann et al, 2015;Homma et al, 2018;Jang et al, 2019). The development of NGS data based CNV calling algorithm makes it possible to identify SNVs and CNVs at same time.…”

“…Recently, multiple researches on clinical utility and cost of WES have provided evidence endorsing it as a first-tier test for children with suspected monogenic disorders (Nguyen and Charlebois, 2015;Monroe et al, 2016;Stark et al, 2016;Hu et al, 2018). CMA has been used as a first-tier clinical diagnostic test in patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) since 2010 (Manning et al, 2010;Miller et al, 2010); and copy number variants (CNVs) detected by CMA explained the pathogenesis for over 10% of these cases (Sanmann et al, 2015;Homma et al, 2018;Jang et al, 2019).…”