Abstract
Precise breakpoint mapping of balanced chromosomal rearrangements is crucial to identify disease etiology. Ten female patients with X-autosome balanced translocations associated with phenotypic alterations were evaluated, by mapping and sequencing their breakpoints. The rearrangements’ impact on the expression of disrupted genes, and inferred mechanisms of formation in each case were assessed. For four patients that presented one of the chromosomal breaks in heterochromatic and highly repetitive segments, we combined cytogenomic methods and short-read sequencing to characterize, at nucleotide resolution, breakpoints that occurred in reference genome gaps. Most of rearrangements were possibly formed by non-homologous end joining and have breakpoints at repeat elements. Seven genes were found to be disrupted in six patients. Six of the affected genes showed altered expression, and the functional impairment of three of them were considered pathogenic. One gene disruption was considered potentially pathogenic, and three had uncertain clinical significance. Four patients presented no gene disruptions, suggesting other pathogenic mechanisms. Four genes were considered potentially affected by position effect and the expression abrogation of one of them was confirmed. This study emphasizes the importance of breakpoint-junction characterization at nucleotide resolution in balanced rearrangements to reveal genetic mechanisms associated with the patients’ phenotypes, mechanisms of formation that originated the rearrangements, and genomic nature of disrupted DNA sequences.
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Acknowledgements
We thank the patients and families, Danilo Moretti-Ferreira, Marco Antonio de Paula Ramos, Rosane Canonaco and Ana Beatriz Alvarez Perez, for the clinical data, and Lausanne Genomic Technologies Facility for technical help.
Funding
This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo [2014/11572-8 to MIM]; and the Swiss National Science Foundation [31003A_160203 to AR]. MMO, ADB and MZ are recipient of a FAPESP fellowship (Fundação de Amparo à Pesquisa do Estado de São Paulo). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Moysés-Oliveira, M., Di-Battista, A., Zamariolli, M. et al. Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes. Eur J Hum Genet 27, 760–771 (2019). https://doi.org/10.1038/s41431-019-0341-5
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DOI: https://doi.org/10.1038/s41431-019-0341-5
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