Absence of heterozygosity accompanying complex human genomic rearrangements: further evidence for replicative mechanisms. C. M. B. C. Fonseca1,2, R. Pfundt3, L. W. Zuccherato1, P. Liu1, P. Stankiewicz1, C. W. Brown1, C. A. Shaw1, G. Ira1, P. J. Hastings1, H. G. Brunner3, J. R. Lupski1, 4, 5 1) Dept Molecular Human Genetics, Baylor Col Medicine, Houston, TX; 2) Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, MG, Brazil;; 3) 3Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 4) Department of Pediatrics, Baylor College of Medicine, Houston, TX; 5) Texas Children's Hospital, Houston, TX.

   Complex genomic rearrangements (CGRs) consist of more than one simple rearrangement with at least two breakpoint junctions formed during the same mutational event. They can consist of deletions, duplications and triplications as well as inversions and complex combinations thereof. Replicative models, such as break-induced replication (BIR), microhomology-mediated break induced replication (MMBIR) and fork stalling and template switching (FoSTeS), feature prominently, but the extent to which they contribute to disease etiology via gene dosage effects, gene interruption at breakpoint junctions, or other mechanisms remains to be unraveled. These replicative mechanisms can more parsimoniously explain the experimental data we observe associated with such complexities. We recently studied four cases of complex rearrangements constituted by duplications interspersed with triplications and associated with absence of heterozygosity (AOH) in the genomic interval distal to the CGR and continuing to the telomere on the same chromosome. These regions of AOH were from 6 Mb to 50.6 Mb in length. Extensive AOH was shown to occur in BIR in yeast if the broken end invades and copies a homologue instead of a sister molecule; it was also predicted to occur in the MMBIR model. We now provide experimental evidence that in humans, complex rearrangements generated postzygotically can lead to regional uniparental disomy (UPD) and that replication-based mechanisms may underlie formation of diverse types of genomic alterations implicated in both constitutional disorders and cancer.

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