AB086. Chromosomal microarray analysis—detection of both duplication and deletion in patients with multiple congenital anomalies and/or developmental delay

Background and objective: Chromosomal microarray analysis (CMA) is recommended as first-tier genetic testing for patients with multiple congenital anomalies, developmental delay/intellectual disability and/or autism spectrum disorder. It detects chromosomal imbalance at a higher resolution than conventional chromosomal analysis. CMA diagnostic service was launched in our hospital in February 2014. The aim of this report is to review the incidence of detecting both duplication and deletion in patients referred for this test.

Methods: DNA was extracted using Gentra Puregene Blood Kit. CMA was performed using the Agilent 4×180 K CGH + SNP array and analysed with Agilent CytoGenomics. G-banding analysis was carried out on stimulated lymphocytes culture. Targeted fluorescence in-situ hybridization (FISH) was performed using locus specific probes.

Results: From 1 February 2014 to 31 May 2015, a total of 205 patients were tested. Seven (3.4%) were identified to have both duplication and deletion of chromosomal segments that were pathogenic [5] or of uncertain clinical significance [2]. We present a case of a 1-day-old Chinese girl with oligohydramnios, prematurity (35+5 weeks) and multiple congenital anomalies including heart defect, cleft palate, ear anomalies, microcephaly, vaginal skin tag, bilateral clinodactyly and wide anterior fontanelle. Karyotyping and FISH analysis for 22q11 deletion were normal. CMA revealed a pathogenic gain of 2.143 Mb at 16p13.3 and a pathogenic loss of 0.271 Mb at 16q24.2q24.3. The gain at 16p13.3 affects 67 genes including CREBBP. The 16p13.3 duplication syndrome is a contiguous gene syndrome characterized by normal to moderate intellectual disability, normal growth, mild arthrogryposis, frequently small and proximally implanted thumbs, characteristic facial features and occasionally, developmental defects of the heart, genitalia, palate or eyes. The 0.271 Mb deletion at 16q24.3 affects four genes including ANKRD11 and CDH15. The clinical features of 16q24.3 microdeletion syndrome include facial dysmorphisms, cognitive impairment, autism, structural anomalies of the brain and seizures. The patient’s reported phenotypes overlap with clinical features seen in both the 16p13.3 duplication syndrome and the 16q24.3 microdeletion syndrome.

Conclusions: CMA helps to identify clinically significant chromosome anomalies that are too small to be detected by karyotyping. Of the seven cases reported with both duplication and deletion, six would not have been picked up by karyotyping. Through CMA, the hospital care team is able to make an accurate genetic diagnosis for the patients.

Keywords: Chromosomal microarray analysis (CMA); 16p13.3 duplication; 16q24.3 microdeletion