Routine Chromosomal Microarray Analysis is Necessary in Korean Patients With Unexplained Developmental Delay/Mental Retardation/Autism Spectrum Disorder

Abstract

BackgroundAll over the world, chromosomal microarray (CMA) is now the first tier diagnostic assay for genetic testing to evaluate developmental delay (DD), mental retardation (MR), and autism spectrum disorder (ASD) with unknown etiology. The average diagnostic yield of the CMA test is known to be about 12.2%, while that of conventional G-banding karyotype is below 3%. This study aimed to assess the usefulness of CMA for the purpose of clinical diagnostic testing in the Korean population.MethodsWe performed CMA and multiplex ligation-dependent probe amplification (MLPA) tests in 96 patients with normal karyotype and unexplained DD, MR, or ASD. The CMA was conducted with CytoScan 750K array (Affymetrix, USA) with an average resolution of 100 kb.ResultsPathogenic copy number variations (CNVs) were detected in 15 patients by CMA and in two patients by MLPA for four known microdeletion syndromes (Prader-Willi/Angelman syndrome, DiGeorge syndrome, Miller-Dieker syndrome and Williams syndrome) designated by National Health Insurance system in Korea. The diagnostic yield was 15.6% and 2.1%, respectively. Thirteen (13.5%) patients (excluding cases with pathogenic CNVs) had variants of uncertain clinical significance. There was one patient with a 17.1-megabase (Mb) region of homozygosity on chromosome 4q.ConclusionsOur findings suggest the necessity of CMA as a routine diagnostic test for unexplained DD, MR, and ASD in Korea.

Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China

“…Moreover, considering the costeffectiveness of CMA compared with that of current conventional cytogenetics and multiplex ligation-dependent probe amplification (MLPA) or FISH, CMA as the first choice in the clinical genetic evaluation of unexplained DD/ ID could be beneficial for patients. 13 Among the 126 cases of pathogenic CNVs, 79 cases were identified as common microdeletion/microduplication syndromes, and 3 cases were rare syndromes, including 15q24 microdeletion syndrome, Xq28 microduplication syndrome and Lowe syndrome. 15q24 microdeletion syndrome is a rare genomic disorder that is characterized by mental retardation, growth retardation, and other structural anomalies, such as congenital heart defects and hypospadias.…”

Multiplex ligation-dependent probe amplification as a screening test in children with autism spectrum disorders

“…Using currently available standard laboratory methods (other than WES or WGS), it is possible to find a genetic cause in about 10% of ASD cases. 11 According to the literature, the aCGH analysis is recommended as a first-tier diagnostic method for ASD patients. 11 Additionally, single-gene tests, such as fragile-X syndrome testing, should be applied.…”

Chromosomal Microarray Testing in 42 Korean Patients with Unexplained Developmental Delay, Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies

“…NHI allows only multiplex ligation-dependent probe amplification tests for four microdeletion syndromes: Angelman/Prader-Willi syndrome, DiGeorge syndrome, Miller-Dieker syndrome, and Williams syndrome [13]. Although subsidies for NGS genetic testing have received government approval this year, NGS tests are limited to a small number of pre-approved diagnostic gene panels.…”