The objective of this one-year Director Award is to continue pathogenic copy number variation (CNV) discovery for exomes generated as part of the SPARK Consortium (the initial work was funded by a SFARI Targeted Award). Evan Eichler and colleagues plan to integrate these results with both de novo single nucleotide variant (SNV) and CNV datasets in order to increase sensitivity for known disease-causing CNVs and to discover novel pathogenic mutations associated with autism.

There are three main aims of the current project: (i) to discover CNVs using two callers, CoNIFER and XHMM, followed by validation using orthogonal microarray data to generate individual calls (PennCNV and cnvPartition [Illumina]) and per-probe copy number using CRLMM; (ii) to integrate with potentially pathogenic de novo SNVs and small insertions/deletions (indels) combining FreeBayes and GATK callsets; and (iii) to compare the results to a previous CNV morbidity map developed in the Eichler lab from individuals with intellectual disability, autism and epilepsy to discover new pathogenic variants. As part of the quality control stage, the researchers plan to identify missed chromosomal aneuploidies and potential misassigned samples.