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

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.

Prenatal Diagnosis of Yq Deletion by Cytogenetic and Fluorescence in Situ Hybridization / 대한주산의학회잡지

OBJECTIVE: The accurate evaluation of a marker chromosome has been limited during prenatal karyotyping. We proposed a method of step-by-step approach to evaluate the origin of a marker chromosome. METHODS: A patient with 19 weeks of gestation was transferred to our hospital for karyotyping due to abnormal Triple test. Karyotyping of amniotic fluid was performed. NOR (nucleolar organizer region) banding and FISH (fluorescence in situ hybridization) using two types of sex chromosome probes: chromosome X alpha satellite probe (DXZI) & chromosome Y alpha satellite probe (DYZ3)(Cytocell, Bambury, UK) and CEP X/Y (Xp11.1-q11.1 CEP X alpha satellite & Yq12 CEP Y satellite III)(Vysis, IL, USA) were done. RESULTS: The routine chromosomal analysis showed 46,X,+mar. As the result of NOR banding, we supposed that the marker chromosome was less likely originated from acrocentric chromosomes. FISH analysis revealed Y centromere signal on marker chromosome, but Yq12 signal was not detected. Therefore the marker chromosome was identified as Y chromosome formed by deletion at Yq11.2. CONCLUSION: This study demonstrated that FISH and NOR banding technique is more effective method for a marker chromosome evaluation during prenatal karyotyping.