Discovery of cryptic chromosomal abnormalities in clinically-referred youth with neuropsychiatric disorders. V. Pillalamarri1,8, A. Doyle1,3,5,6,8, H. Brand1,5, M. R. Stone1, I. Blumenthal1, C. O'dushlaine3, E. Braaten5, J. Rosenfeld7, S. McCarroll3,4,6, J. Smoller1,2,5, M. E. Talkowski1,3,5 1) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 2) Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital; 3) Program in Medical and Population Genetics, Broad Institute of MIT and Harvard; 4) Department of Genetics, Harvard Medical School; 5) Departments of Psychiatry, Neurology, Harvard Medical School; 6) Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; 7) Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA; 8) Co-First Author.

   Unequivocal evidence suggests that rare structural variation (SV) is among the strongest genetic risk factors for neuropsychiatric disorders (NPD), including autism and schizophrenia. Recently, we showed that balanced chromosomal abnormalities (BCAs) detected at cytogenetic resolution represent a unique class of highly penetrant SV resulting in heterozygous inactivation at a single point in the genome. To date, the impact of submicroscopic BCAs have not been routinely investigated as they remain cryptic to all conventional technologies other than deep whole-genome sequencing (WGS). Here, we define the landscape of cryptic BCAs in a clinically-referred youth cohort with NPDs, including autism and early onset psychiatric phenotypes as part of a longitudinal data collection. We sequenced 33 subjects using customized large-insert or jumping library WGS to a median insert coverage of ~60x with an insert size of ~2.6kb. We find 98.1% sensitivity to detect cryptic BCAs. We used a convergent genomic approach to support the broader significance of associated loci by comparing copy number variant (CNV) data from over 34,000 clinical diagnostic cases and 14,000 controls, as well as existing GWAS and exome data. Our approach uncovered a spectrum of BCAs including intra-chromosomal inverted insertions, inter-chromosomal excision/insertion and exchange events, and semi-balanced BCAs with small CNVs at the breakpoint. As expected, ~55-65% of cryptic BCAs represent differences from the reference assembly and are observed in all individuals with adequate coverage. Across 33 subjects, we detected about 50 balanced exchanges per individual, with most events being polymorphic. However, we observed 10 genes and one microRNA (mir1256) that were disrupted by a private cryptic BCA and not observed in other individuals. All events were validated by PCR and the parental origin was evaluated. Convergent genomics and network analyses implicated four of these loci, each with a direct, first-order interaction to a previously implicated ASD locus (AKAP13, IQGAP1, ETV4, CTNNA3), as well as a putative novel locus (UBE2F; CNV burden p = 8.3x10-4). For CTNNA3, we discovered an upstream disruption by a reciprocal translocation in a second independent case with ASD. We note as many as five putative contributors to the phenotypes of 33 patients. These data suggest that cryptic BCAs are an important and uncharacterized component of the genetic architecture of NPDs.

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