Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, Hunan, China.
Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410023, Hunan, China.
J Assist Reprod Genet. 2024 Jan;41(1):147-159. doi: 10.1007/s10815-023-02986-7. Epub 2023 Nov 23.
To report genetic characteristics and associated risk of chromosomal breaks due to chromosomal rearrangements in large samples.
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.
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.
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.
在大样本中报告由于染色体重排导致的染色体断裂的遗传特征和相关风险。
采用 MicroSeq 技术，结合染色体微切割和下一代测序，鉴定染色体断裂点。长距离 PCR 和 Sanger 测序用于精确表征 50 名 ABCR 携带者中的 100 个断裂点。
除了已经记录的平衡重排断裂的常见区域 8q24.13、11q11.23 和 22q11.21 之外，我们还发现了一个可能是平衡重排断裂稀疏区域的 12q24.13-q24.3 的 10-Mb 区域。我们发现 898 个断裂点导致基因中断，总共 188 个断裂点中断了 OMIM 中记录的基因。在 OMIM 中，中断常染色体显性基因的断裂点百分比为 25.53%（48/188）。精确表征的 54 个断裂点具有 1-8-bp 微同源序列。
我们的发现为评估临床实践中导致蛋白质截断的相关基因突变的致病性提供了参考。根据断裂点的特征，非同源末端连接和微同源介导的断裂诱导复制可能是 ABCR 形成的主要机制。
