Novel copy-number variants in a population-based investigation of classic heterotaxy

Heterotaxy is a clinically and genetically heterogeneous disorder. We investigated whether screening cases restricted to a classic phenotype would result in the discovery of novel, potentially causal copy-number variants. We identified 77 cases of classic heterotaxy from all live births in New York State during 1998–2005. DNA extracted from each infant’s newborn dried blood spot was genotyped with a microarray containing 2.5 million single-nucleotide polymorphisms. Copy-number variants were identified with PennCNV and cnvPartition software. Candidates were selected for follow-up if they were absent in unaffected controls, contained 10 or more consecutive probes, and had minimal overlap with variants published in the Database of Genomic Variants. We identified 20 rare copy-number variants including a deletion of BMP2, which has been linked to laterality disorders in mice but not previously reported in humans. We also identified a large, terminal deletion of 10q and a microdeletion at 1q23.1 involving the MNDA gene; both are rare variants suspected to be associated with heterotaxy. Our findings implicate rare copy-number variants in classic heterotaxy and highlight several candidate gene regions for further investigation. We also demonstrate the efficacy of copy-number variant genotyping in blood spots using microarrays. Genet Med 17 5, 348–357.