Dataset Information

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

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.

SUBMITTER: Moyses-Oliveira M

PROVIDER: S-EPMC6461923 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Moysés-Oliveira Mariana M Di-Battista Adriana A Zamariolli Malú M Meloni Vera Ayres VA Bragagnolo Silvia S Christofolini Denise Maria DM Steiner Carlos Eduardo CE Kosyakova Nadezda N Liehr Thomas T Reymond Alexandre A Melaragno Maria Isabel MI

European journal of human genetics : EJHG 20190130 5

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 ...[more]

PMID: 30700833

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Project description:Familial apparently balanced translocations (ABTs) segregating with discordant phenotypes are extremely challenging for interpretation and counseling due to the scarcity of publications and lack of routine techniques for quick investigation. Recently, next generation sequencing has emerged as an efficacious methodology for precise detection of translocation breakpoints. However, studies so far have mainly focused on de novo translocations. The present study focuses specifically on familial cases in order to shed some light to this diagnostic dilemma. Whole-genome mate-pair sequencing (WG-MPS) was applied to map the breakpoints in nine two-way ABT carriers from four families. Translocation breakpoints and patient-specific structural variants were validated by Sanger sequencing and quantitative Real Time PCR, respectively. Identical sequencing patterns and breakpoints were identified in affected and non-affected members carrying the same translocations. PTCD1, ATP5J2-PTCD1, CADPS2, and STPG1 were disrupted by the translocations in three families, rendering them initially as possible disease candidate genes. However, subsequent mutation screening and structural variant analysis did not reveal any pathogenic mutations or unique variants in the affected individuals that could explain the phenotypic differences between carriers of the same translocations. In conclusion, we suggest that NGS-based methods, such as WG-MPS, can be successfully used for detailed mapping of translocation breakpoints, which can also be used in routine clinical investigation of ABT cases. Unlike de novo translocations, no associations were determined here between familial two-way ABTs and the phenotype of the affected members, in which the presence of cryptic imbalances and complex chromosomal rearrangements has been excluded. Future whole-exome or whole-genome sequencing will potentially reveal unidentified mutations in the patients underlying the discordant phenotypes within each family. In addition, larger studies are needed to determine the exact percentage for phenotypic risk in families with ABTs.

Project description:Bilateral renal agenesis/hypoplasia/dysplasia (BRAHD) is a relatively common, lethal malformation in humans. Established clinical risk factors include maternal insulin dependent diabetes mellitus and male sex of the fetus. In the majority of cases, no specific etiology can be established, although teratogenic, syndromal and single gene causes can be assigned to some cases.45 unrelated fetuses, stillbirths or infants with lethal BRAHD were ascertained through a single regional paediatric pathology service (male:female 34:11 or 3.1:1). The previously reported phenotypic overlaps with VACTERL, caudal dysgenesis, hemifacial microsomia and Müllerian defects were confirmed. A new finding is that 16/45 (35.6%; m:f 13:3 or 4.3:1) BRAHD cases had one or more extrarenal malformations indicative of a disoder of laterality determination including; incomplete lobulation of right lung (seven cases), malrotation of the gut (seven cases) and persistence of the left superior vena cava (five cases). One such case with multiple laterality defects and sirelomelia was found to have a de novo apparently balanced reciprocal translocation 46,XY,t(2;6)(p22.3;q12). Translocation breakpoint mapping was performed by interphase fluorescent in-situ hybridization (FISH) using nuclei extracted from archival tissue sections in both this case and an isolated bilateral renal agenesis case associated with a de novo 46,XY,t(1;2)(q41;p25.3). Both t(2;6) breakpoints mapped to gene-free regions with no strong evidence of cis-regulatory potential. Ten genes localized within 500 kb of the t(1;2) breakpoints. Wholemount in-situ expression analyses of the mouse orthologs of these genes in embryonic mouse kidneys showed strong expression of Esrrg, encoding a nuclear steroid hormone receptor. Immunohistochemical analysis showed that Esrrg was restricted to proximal ductal tissue within the embryonic kidney.The previously unreported association of BRAHD with laterality defects suggests that renal agenesis may share a common etiology with heterotaxy in some cases. Translocation breakpoint mapping identified ESRRG as a plausible candidate gene for BRAHD.

Dataset Information

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

Publications

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

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