Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes

Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here, we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed three duplications and three triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis‐like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline‐level event in the proband's maternal grandmother. Whole‐genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life‐cycle genesis, and propose a DNA replicative/repair mechanism underlying formation. Small supernumerary maker chromosomes (sSMC) are chromosomal fragments difficult to genomically characterize. In a familial sSMC that segregates with pleiotropic psychiatric phenotypes we used multiple genomic technologies to identify and fine map structural variants, determine the breakpoint junctions, and delineate the precise architecture of this sSMC.