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. 2024 Jan;41(1):147-159.
doi: 10.1007/s10815-023-02986-7. Epub 2023 Nov 23.

Evaluation of genetic risk of apparently balanced chromosomal rearrangement carriers by breakpoint characterization

Yanqin Xiao  1 , Dehua Cheng  2 , Keli Luo  1   2 , Mengge Li  3   4 , Yueqiu Tan  1   2 , Ge Lin  1   2   3   5 , Liang Hu  6   7   8   9
Affiliations

Evaluation of genetic risk of apparently balanced chromosomal rearrangement carriers by breakpoint characterization

Yanqin Xiao et al. J Assist Reprod Genet. 2024 Jan.

Abstract

Purpose: To report genetic characteristics and associated risk of chromosomal breaks due to chromosomal rearrangements in large samples.

Methods: MicroSeq, a technique that combines chromosome microdissection and next-generation sequencing, was used to identify chromosomal breakpoints. Long-range PCR and Sanger sequencing were used to precisely characterize 100 breakpoints in 50 ABCR carriers.

Results: In addition to the recurrent regions of balanced rearrangement breaks in 8q24.13, 11q11.23, and 22q11.21 that had been documented, we have discovered a 10-Mb region of 12q24.13-q24.3 that could potentially be a sparse region of balanced rearrangement breaks. We found that 898 breakpoints caused gene disruption and a total of 188 breakpoints interrupted genes recorded in OMIM. The percentage of breakpoints that disrupted autosomal dominant genes recorded in OMIM was 25.53% (48/188). Fifty-four of the precisely characterized breakpoints had 1-8-bp microhomologous sequences.

Conclusion: Our findings provide a reference for the evaluation of the pathogenicity of mutations in related genes that cause protein truncation in clinical practice. According to the characteristics of breakpoints, non-homologous end joining and microhomology-mediated break-induced replication may be the main mechanism for ABCRs formation.

Keywords: Breakpoint; Chromosome rearrangement; Genetic risk; MicroSeq.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Distribution of breakpoints on chromosomes. a Distribution of breakpoints on chromosomes other than sex chromosomes. b Distribution of breakpoints on chromosome 22 shows a recurrent breakpoint region of 22q11.21. c Distribution of breakpoints on chromosome 8 shows a recurrent breakpoint region of 8q24.13. d Distribution of breakpoints on chromosome 11 shows a recurrent breakpoint region of 11q11.23. e Distribution of breakpoints on chromosome 12 shows a large sparse region of q24.13-q24.3. f Distribution of breakpoints on chromosome 9 shows a large breakpoint gap of 9q12 due to the presence of heterochromatin
Fig. 2
Fig. 2
Distribution of the recurrent translocation rearrangement breakpoints mapped in our research. The chromosome exchange between 11q23.3 and 22q11.21 was highlighted in red
Fig. 3
Fig. 3
Classification of breakpoints location. a Classifications of breakpoints located in specific euchromatin. b Proportion of 2102 breakpoints which can be determine whether the genes are disrupted. c Classifications of diseases associated with the 48 AD genes which were interrupted by breakpoints. Red font indicates that the genes belong to haploinsufficiency genes
Fig. 4
Fig. 4
Molecular characterization of 100 precise breakpoints. a Schematic representation of types of chromosomal equilibrium rearrangements. i Flat end joining; ii schematic representation of end joining containing only microhomology; iii schematic representation of end joining containing microhomology accompanied by insertion or deletion. b Bar chart of classification of 100 precise breakpoint characters
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