Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes

Autor(es):Mostrar menos -

Moyses-Oliveira, Mariana ^[1] ; Di-Battista, Adriana ^[1] ; Zamariolli, Malu ^[1] ; Meloni, Vera Ayres ^[1] ; Bragagnolo, Silvia ^[1] ; Christofolini, Denise Maria ^[2] ; Steiner, Carlos Eduardo ^[3] ; Kosyakova, Nadezda ^[4] ; Liehr, Thomas ^[4] ; Reymond, Alexandre ^[5] ; Melaragno, Maria Isabel ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Div Genet, Dept Morphol & Genet, BR-04023900 Sao Paulo - Brazil

^[2] Fac Med ABC, Dept Collect Hlth, Human Reprod & Genet Ctr, Santo Andre, SP - Brazil

^[3] Univ Estadual Campinas, Sch Med Sci, Dept Med Genet, Campinas, SP - Brazil

^[4] Friedrich Schiller Univ, Jena Univ Hosp, Inst Human Genet, D-07747 Jena - Germany

^[5] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne - Switzerland

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Human Genetics; v. 27, n. 5, p. 760-771, MAY 2019.
• Citações Web of Science: 0

Resumo

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 nonhomologous 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. (AU)

• Processo FAPESP: 14/11572-8 - Rearranjos cromossômicos e sua importância na etiologia das doenças genéticas: investigação citogenômica e molecular
• Beneficiário: Maria Isabel de Souza Aranha Melaragno
• Modalidade de apoio: Auxílio à Pesquisa - Temático