Cryptic Chromosomal Aberrations Contributing to Autism

Half a century ago, the introduction of karyotyping transformed human genetics and clinical diagnostics by opening access to gross changes in the chromosomes, revealing an entire class of previously undetectable genetic lesions. Microarrays revealed that DNA gains and losses can cause genetic disease; however, the rate of return of significant findings from genomic microarray is quite low, with over 80% of clinical referrals yielding unremarkable or inconclusive genomic profiles. Similarly, even in extensively studied common complex diseases such as autism, the fraction of genetic contribution not explained by conventional association methods remains quite large. This project brought together leading experts in genomics, statistics, clinical diagnostics, and computational genetics to open access to another potentially critical class of genomic variation that remains unseen to all current methods of gene discovery in autism: chromosomal rearrangements that do not involve gains and losses of DNA. Previous research suggests this class of ‘cryptic’ alterations (or not visible at microscopic resolution) can have a profound impact in autism, ranging from small microinversions that directly inactivate the message of a single gene to highly complicated shattering and reorganization of chromosomes in autism cases that went completely unnoticed by current gold standards in clinical diagnostics. Dr. Talkowski’s group performed an innovative form of whole-genome sequencing to identify all classes of structural variations at an order of magnitude lower cost than standard whole-genome sequencing, enabling access to a large number of cases at modest overall cost.