Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination

Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in genomic disorders, such as the 3q29 deletion syndrome. At the 3q29 region, non-allelic homologous recombination (NAHR) between paralogous copies of segmental duplications (SDs) leads to a recurrent [~]1.6 Mbp deletion or duplication, causing neurodevelopmental and psychiatric phenotypes. However, risk factors contributing to NAHR at this locus are not well understood. In this study, we used an optical mapping approach to identify structural variations within the 3q29 interval. We identified 18 novel haplotypes among 161 unaffected individuals and used this information to characterize this region in 18 probands with either the 3q29 deletion or 3q29 duplication syndrome. A significant amount of variation in haplotype prevalence was observed between populations. Within probands, we narrowed down the breakpoints to a [~]5 kbp segment within the SD blocks in 89% of the 3q29 deletion and duplication cases studied. Furthermore, all 3q29 deletion and duplication cases could be categorized into one of five distinct classes based on their breakpoints. Contrary to previous findings for other recurrent deletion and duplication loci, there was no evidence for inversions in either parent of the probands mediating the deletion or duplication seen in this syndrome.