Objectives: We are utilizing copy number data from cytogenetic arrays to build a CNV Atlas for Autism to be used as a gene discovery and clinical research tool.
Methods: We have analyzed data from >15,500 whole-genome cytogenetic arrays from seven clinical diagnostic laboratories that are members of the International Standard Cytogenomic Array (ISCA) consortium. Approximately 15% of patients referred for clinical cytogenetic array testing have a primary indication of autism or ASD.
Results: Key results of our preliminary analysis relevant to autism include: 1) Microdeletion 16p11.2 is the second most common imbalance observed in all children referred for clinical array testing, observed in ~1/250 cases. Many of these children were referred in the first few years of life due to developmental delay and provide an opportunity for studies of early natural history and intervention. 2) Microdeletion 17q12, previously described in association with renal anomalies and diabetes, was identified in 10 cases and led to the delineation of a new syndromic phenotype including macrocephaly, characteristic facial appearance, and autism in males (6/6) but not females (0/3). Previous linkage and association studies, replicated by multiple groups, suggested a “male-only” peak in this same region of 17q, indicating a sex-specific locus for autism. 3) Review of small, de novo deletions in children with an indication of autism/ASD revealed a number of cases (n=22) in which only 1 or two genes were contained within the deleted segment, providing a highly efficient deletion mapping strategy for identification of autism candidate genes. A recently funded NIH Grand Opportunity (GO) grant will allow development and expansion of a CNV database from clinical cytogenetic testing with an estimated 200,000 cases within the next two years.
Conclusions: This free, public database will be a significant resource for the identification of candidate genes for autism and other developmental disorders, and allow detailed genotype-phenotype correlation studies for human CNVs.