International Meeting for Autism Research: Genomic Copy Number Variation in Pediatric Patients with Autism Spectrum Disorders

Genomic Copy Number Variation in Pediatric Patients with Autism Spectrum Disorders

Saturday, May 22, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
10:00 AM
E. A. Varga , Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH
D. Lamb-Thrush , Cytogenetics/Molecular Genetics, Nationwide Children's Hospital
C. Astbury , Cytogenetics/Molecular Genetics, Nationwide Children's Hospital
R. Pyatt , Cytogenetics/Molecular Genetics, Nationwide Children's Hospital
S. Reshmi , Cytogenetics/Molecular Genetics, Nationwide Children's Hospital
J. Gastier-Foster , Cytogenetics/Molecular Genetics, Nationwide Children's Hospital
G. E. Herman , Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH
Background: Microarray-based comparative genomic hybridization (aCGH) is increasingly utilized in the genetic evaluation of children with autism spectrum disorders (ASDs).  There is some controversy regarding the use of oligonucleotide arrays in clinical practice, as testing with this level of resolution may increase detection of likely benign copy number variation (bCNV) or CNV of unknown significance (uCNV), but not necessarily pathogenic CNVs (pCNVs).
Objectives:  To describe our clinical laboratory experience in offering aCGH testing for an indication of ASD and determine if choice of array platform impacts number of bCNVs, uCNVs and pCNVs reported.
Methods: Our cytogenetics and molecular genetics laboratory performed aCGH on 530 unique subjects for a clinical indication of ASD between 1/1/2007 and 6/30/2009.  Various aCGH platforms were used including bacterial artificial chromosome (BAC) arrays containing 600, 1887, and 4670 probes and an oligonucleotide (oligo) array containing 105,000 probes. To interpret the significance of CNVs, we evaluated the size and type of the rearrangement (deletion vs. duplication), inheritance and gene content. Insights were gained from the literature where possible and from databases, including the Database of Genomic Variants, the UCSC Genome Browser, and an internal institutional CNV database.
Results: Of 530 subjects, 320 (60%) were tested on a BAC aCGH and 210 (40%) were tested on an oligo aCGH platform.  Four subjects were tested to clarify abnormalities identified previously on chromosome analysis and were excluded from subsequent analysis. Of the 526 subjects remaining, 129 (25%) had a  reported CNV. Fifty-two of these (40%) were interpreted as a bCNV; 57 (44%) had at least one uCNV; and 20 (16%) had at least one pCNV.   Twenty-one subjects (16%) had >1 reported CNV. Significantly more abnormalities were reported on oligo aCGH compared to BAC array (68/210 vs. 61/320, p<0.001),  likely due to the fact that significantly more bCNVs were reported on oligo vs. BAC array  (32 vs. 20, p<0.001).  The number of reported uCNVs and pCNVs did not differ between array types (uCNV= 29 oligo vs. 28 BAC, p>0.10; pCNV= 7 oligo vs. 13 BAC, p>0.50). Recurrent pCNVs included a duplication (dup) and two deletions (del) of 22q11.21 (DiGeorge region); del and dup1q21.1, and 2 duplications of Xq28 including the MeCP2 gene.  Other pCNVs contained genes previously implicated in autism including, but not limited to, NRNX1, NLGN4, SHANK3, ELN, and CNTN4
Conclusions: Our findings suggest that both BAC and oligo aCGH testing of subjects with ASD is beneficial to identify pCNVs, which may assist in genetic counseling.  Further investigation of uCNVs, found in a large proportion of our population, may help delineate genes and molecular pathways which play a role in ASD susceptibility.  Our laboratory experience confirms that more bCNVs may be reported on oligo array compared to BAC arrays.
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