Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay

Abstract

Purpose: Recent advancements in molecular techniques have greatly contributed to the discovery of genetic causes of unexplained developmental delay. Here, we describe the results of array comparative genomic hybridization (CGH) and the clinical features of 27 patients with global developmental delay.

Methods: We included 27 children who fulfilled the following criteria: Korean children under 6 years with global developmental delay; children who had at least one or more physical or neurological problem other than global developmental delay; and patients in whom both array CGH and G-banded karyotyping tests were performed.

Results: Fifteen male and 12 female patients with a mean age of 29.3±17.6 months were included. The most common physical and neurological abnormalities were facial dysmorphism (n=16), epilepsy (n=7), and hypotonia (n=7). Pathogenic copy number variation results were observed in 4 patients (14.8%): 18.73 Mb dup(2)(p24.2p25.3) and 1.62 Mb del(20p13) (patient 1); 22.31 Mb dup(2) (p22.3p25.1) and 4.01 Mb dup(2)(p21p22.1) (patient 2); 12.08 Mb del(4)(q22.1q24) (patient 3); and 1.19 Mb del(1)(q21.1) (patient 4). One patient (3.7%) displayed a variant of uncertain significance. Four patients (14.8%) displayed discordance between G-banded karyotyping and array CGH results. Among patients with normal array CGH results, 4 (16%) revealed brain anomalies such as schizencephaly and hydranencephaly. One patient was diagnosed with Rett syndrome and one with Möbius syndrome.

Conclusion: As chromosomal microarray can elucidate the cause of previously unexplained developmental delay, it should be considered as a first-tier cytogenetic diagnostic test for children with unexplained developmental delay.

Keywords: Child; Comparative genomic hybridization; Developmental disabilities; Karyotyping.

Fig. 1. Genetic features of patient 1. (A) G-banded karyotyping shows 46,XY,dup(20)(p13) (arrow). (B) Array comparative genomic hybridization shows an 18.73-Mb duplication of 2p24.2-2p25.3 (red region) and 1.62-Mb deletion of 20p13 (blue region), (C, D) Fluorescence in situ hybridization indicates a rearrangement resulting from fusion of the duplicated 2p terminal to the deleted 20p terminal. Bacterial artificial chromosome (BAC) RP11-480N14 (red) harbors the 2p24.3 location and BAC RP11-314N13 (green) harbors the 20p13 location.

Fig. 2. Genetic features of patient 2. (A) G-banded karyotyping shows 46,XY,dup(2)(p21p25.1) in this panel (arrow). However, patient 2 had low-level mosaicism (11.5%) of 46,XY,dup(2)(p21p25.1[177]/46,XY,del(2)(p22p23)[23]) in G-banded karyotyping. (B) Array comparative genomic hybridization (CGH) shows a 22.31-Mb duplication of 2p22.3-2p25.1 and 4.01-Mb duplication of 2p21-2p22.1 (red regions). Array CGH analysis did not show low-level mosaicism, but was able to identify that the large duplication of dup(2)(p21p25.1) observed in G-banded karyotyping was actually composed of two separate duplications (2p21-2p22.1 and 2p22.3-2p25.1), whereas the copy number of the intermediate genomic sequence was normal. (C) Fluorescence in situ hybridization (FISH) indicates 2p24.3 duplication (RP11-480N14, red color), and normal copy number of 2q22.3 (RP11-141C15, green color). (D) FISH also indicates 2p21 duplication (RP11-20A12, red color).