Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services

Abstract

Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105 K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4 years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.

Keywords: A2BP1; ACADL; ACOXL; ADIPOQ; ALS2 chromosome region gene 8; ALS2CR8; ANKRD11; ANOVA; ASD; Autism spectrum disorders (ASD); BAC; BCL2-like 11 gene; BCL2L11; CACNA1C; CHRNA7; CNV; COBL; CT; Chromosomal microarray analysis; Copy number variant (CNV); DLG1; DLG4; DNA; Developmental delay; EEF1B2; EEG; F-box only 45 gene; FAM117B; FAT tumor suppressor 1 gene; FAT1; FBXO45; FISH; FXR2; FZD5; GALR1; GATA zinc finger domain-containing protein 2B gene; GATAD2B; GDNF-inducible zinc finger protein 1 gene; GZF1; HAX1; HCLS1-associated protein X1 gene; HDAC; IDH1; IL1RAPL1; ITPR1; KLF7; KNG1; LINS; LMNA; Learning disability; MAP2; MBP; MRPL19; MYL1; NADH-ubiquinone oxidoreductase Fe-S protein 1 gene; NDUFS1; NLGN2; NPHP1; NRXN1; PAK2; PARK2; PMP22; POLG; PRPF8; PTEN; PTH2R; RPE; SACS; SD; SH2B adaptor protein 1 gene; SH2B1; SH3 and multiple ankyrin repeat domains 3 gene; SHANK3; SHOX; SMARCA4; STAG2; SUMF1; SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member gene; TRAPPC2; UCSC; USP6; University of California, Santa Cruz; X-linked inhibitor of apoptosis gene; XIAP; YWHAE; ZNF407; aCGH; acyl-coA dehydrogenase, long chain gene; acyl-coA oxidase-like gene; adipocyte-, C1q-, and collagen domain containing gene; analysis of variance; ankyrin repeat domain-containing protein 11 gene; array comparative genomic hybridization; ataxin 2-binding protein 1 gene; autism spectrum disorder; bacterial artificial chromosome; calcium channel, voltage dependent, L-type, alpha 1C subunit gene; cholinergic receptor, neuronal nicotinic, alpha polypeptide 7 gene; computed tomography; copy number variant; cordon-bleu gene; deoxyribonucleic acid; discs, large homolog 1 gene; discs, large homolog 4 gene; electroencephalogram; eukaryotic translation elongation factor 1, beta-2 gene; family with sequence similarity 117, member B gene; fluorescence in situ hybridization; fragile X mental retardation, autosomal homolog 2 gene; frizzled 5 gene; galanin receptor 1 gene; histone deacetylase gene; inositol 1,4,5-triphosphate receptor, type 1 gene; interleukin 1 receptor accessory protein-like 1 gene; isocitrate dehydrogenase 1 gene; kininogen 1 gene; kruppel-like factor 7 gene; lamin A gene; lines homolog gene; microtubule-associated protein 2 gene; mitochondrial ribosomal protein L19 gene; myelin basic protein gene; myosin, light peptide 1 gene; nephrocystin 1 gene; neurexin 1 gene; neuroligin 2 gene; parathyroid hormone receptor 2 gene; parkin gene; peripheral myelin protein 22 gene; phosphatase and tensin homolog gene; polymerase gamma gene; precursor mRNA-processing factor 8 gene; protein-activated kinase 2 gene; ribulose 5-phosphate 3-epimerase gene; sacsin gene; short stature homeobox gene; standard deviation; stromal antigen 2 gene; sulfatase-modifying factor 1 gene; tracking protein particle complex, subunit 2 gene; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon isoform gene; ubiquitin-specific protease 6 gene; zinc finger protein 407 gene.