All ETDs from UAB

Advisory Committee Chair

Ludwine M Messiaen

Advisory Committee Members

Bruce R Korf

Fady M Mikhail

Kai Jiao

Arkadiusz Piotrowski

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Genomic rearrangements may cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements have been proposed such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR). However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number changes (CNCs) remains understudied. Furthermore, only few studies resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array Comparative Genomic Hybridization (aCGH), we have identified the breakpoints and characterized the likely rearrangement mechanism of the NF1 intragenic CNCs in 85 unrelated patients. Unlike the most typical recurrent rearrangements mediated by flanking low copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location and rearrangement mechanisms. We propose the DNA replication-based mechanisms comprising FoSTeS/MMBIR and serial replication stalling to be the predominant mechanism leading to NF1 intragenic CNCs. Within intron 40 of the NF1 gene, a 197-bp long palindromic AT-rich repeat (PATRR17) has been identified as intragenic rearrangement hotspot leading to 6 deletions and one chromosomal translocation t(14;17)(q32;q11.2). Although previous studies indicated a purely replication-independent mechanism for PATRR-mediated translocations, the PATRR17-mediated intragenic deletions as well as the translocation are most likely the result of a replication-dependent mechanism. In addition to PATRR17, four Alu elements located in intron 1, 2, 3 and 50 were also identified as significant intragenic rearrangement hotspots within the NF1 gene.



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