Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
10:00 AM
D. Salyakina
,
John P Hussman Institute for Human Genomics, University of Miami, Miami, FL
H. N. Cukier
,
John P Hussman Institute for Human Genomics, University of Miami, Miami, FL
D. Ma
,
Human Genetics, Hussman Institute for Human Genomics, Miami, FL
J. Jaworski
,
Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
I. Konidari
,
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL
J. Gilbert
,
Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
M. L. Cuccaro
,
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL
M. A. Pericak-Vance
,
Human Genetics, Hussman Institute for Human Genomics, Miami, FL
Background:
Recent research has suggested that inheritance for idiopathic autism (IA, with one individual in the family affected) may be distinct from inheritance for multiplex autism (MA, with two or more individuals in the family affected). Rare copy number variations (CNV) have been associated with autism, but these have been observed more commonly in IA than in MA. In contrast, interactive effects in multiple common susceptibility alleles have been hypothesized as causes of familial autism.Objectives:
The lack of association of CNVs with autism in multiplex families could be explained by the limitation of previous studies to relatively large CNVs. New genotyping platforms such as Illumina offer dense marker coverage, which allow testing for CNVs with lengths of several kilo bases. In order to explore the role of CNVs in autism we used two approaches: testing for association of all common CNVs in a unique data set including affected and unaffected members of extended families; as well as screening for rare CNVs segregating all affecteds within individual families. Methods:
45 extended families with 2 or more children affected with autism were available for analysis. Samples were genotyped using Illumina’s Human 1M Beadchip, containing 1,072,820 SNPs. Samples and markers with call rates below 95% were excluded from analysis. We excluded from the analysis all CNV that did not demonstrate clear inheritance within the families.We used the PennCNV algorithm for CNV calling. Quality control was performed as recommended by the PennCNV algorithm authors. Association was tested using the pedigree disequilibrium test (PDT). CNV validation was performed in quadruplicates using Applied Biosystems Taqman Copy Number Assays. Results:
In total, 13168 CNVs in 471 genomes passed all QC steps, 14948 of which had unique boundaries. Common deletions on chromosome 6p21.32 in C4A and C4B genes localized in the major histocompatibility complex (MHC) class III region on chromosome 6 showed association with autism (p-value = 0.0026). This association possibly implies etiological mechanisms involving autoimmunity and/or infection. Validation of CNVs in this region is ongoing.
Six regions on chromosomes 4p16.3, 6q11.1, 7p21.2, 10p12.31, 13q31.1, 15q24.1 showed perfect segregation with incomplete penetrance, each in one family. None of these six regions have been reported in the Database of Genomic Variants (DGV). The length of these CNVs varied from 5.2 to 348.5 kb. 3 of 6 regions were validated (4p16.3, 6q11.1, 10p12.31) with real time PCR, with the concordance rate between predicted and validated CNVs in tested assays 100%. The validation of remaining 3 CNV regions is ongoing.
Conclusions:
In our study we found a novel region on chromosome 6p21.32 to be associated with autism, as well as six rare CNVs segregating in autistic families. We were able to validate 3 of these rare CNVs with extremely high consistency. Our results confirm the heterogeneous nature of autism and suggest that, probably, both common and rare CNVs are involved in its etiology.
