Replication-based mechanism underlies a complex dup(18p)/del(18q) rearrangement not derived from parental inversion

Introduction: Most intrachromosomal rearrangements characterized by terminal monosomy and trisomy concomitantly seen in different arms of the same chromosome usually arise due to pericentric inversions in parents. Forty-seven patients have been described with such alteration in chromosome 18. Methods: We investigated a patient with dup(18p)/del(18q) whose rearrangement was characterized by karyotype, catalog and custom chromosomal microarrays, fluorescence in situ hybridization (FISH), whole genome sequencing, and Sanger sequencing. Results: The patient presents a 9.7 Mb terminal duplication in 18p and a 25.8 Mb terminal deletion in 18q. The duplicated segment is inserted into the long arm of chromosome 18 in an inverted position. At the junction point, we found a 19-nucleotide segment insertion derived from a downstream 18q sequence and the presence of microhomology with both the breakpoint from the long-arm region and the one from the inverted duplicated segment from the short arm. Conclusion: We described, to the best of our knowledge, the fifth confirmed case of concomitant terminal trisomy and monosomy in different arms of chromosome 18 which is not due to a pericentric parental inversion, and the first with breakpoints determined at nucleotide level. The combination of various techniques enabled us to infer the rearrangement’s likely mechanism of formation. The structural features observed are consistent with replication-based mechanisms, including Fork Stalling and Template Switching (FoSTeS) and Microhomology-Mediated Break-Induced Replication (MMBIR). The detailed rearrangement characterization also allowed for a more detailed karyotype-phenotype correlation, which indicates that the 18q deletion is likely the cause of most of the patient’s phenotypical alterations.