Abstracts

Rationale: The last 5 years has seen an explosion of the number of genes and loci that are associated with Infantile Spasms syndrome, but for many cases an etiology remains elusive. While there has been a shift from single nucleotide polymorphism (SNP) and/or comparative hybridization array technologies to whole exome sequencing methods the power of SNP arrays to make genetic diagnoses and/or localize involved loci remains the first line of genetic diagnosis. As part of on going studies at the Center for Applied Genomics at CHOP, over 120 patients with a diagnosis of Infantile Spasms (IS) were recruited and genotyped using SNP arrays. We subsequently performed a genome wide association study of the CNV and SNP data and now present a number of potential new loci that reached genome wide significance in our cohort. Methods: 120 cases from CHOP and 18 cases submitted from the University of Chicago were analyzed on the InfiniumII HumanHap610 BeadChip technology (Illumina San Diego CA), at the Center for Applied Genomics at Children's Hospital of Philadelphia (CHOP). 7185 healthy controls were analyzed on the same platform and compared to the IS patients. Chart review of the 120 cases was performed to confirm a diagnosis of ISS and extract data about etiology and epilepsy outcome. A selected gene association study was also performed against a set of genes known to be enriched during interneuron development. Results: After review of the 120 cases marked as IS by ICD9 codes, 62 had evidence of infantile spasms and/or hypsarrhythmia. All 18 cases from the University of Chicago had IS. In these 62 cases, there were 5 cases with CNVs that reached genome wide significance and 6 others with which were in 2 patients and no controls but only trended toward genome wide significance. Both deletions (16q26-27; 7q33) and duplications (15q11-12; 21q22.3) were present in this group. In addition, there were many rare variants found in the IS population, some of which were in known loci. Rare CNVs were found in 41/79 IS patients with a number known genes/loci revealed. As expected a genome wide association study did not reach significance for any SNP due to the small number of patients. The selected gene association study using known interneuron development genes found 3 loci with statistically significant association. Conclusions: We performed a genome-wide association study for CNVs and SNPs in a sample of patients with Infantile Spasms. Multiple CNVs including 15q11-12 duplications reach genome-wide significance and we uncovered various single rare pathogenic CNVs in this population. A genome-wide association study based on SNPs validated some recently described genes as well as a some of the significant CNVs found in this study. Our data reaffirms the utility of SNP arrays to both diagnose patients with ISS as well as discover new loci that may be associated with IS.