Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Genes (Basel). 2022 Sep 17;13(9):1668. doi: 10.3390/genes13091668.
The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual's 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual's risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father's normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion.
人类群体中最常见的微缺失发生在 22q11.2，这一区域富含染色体特异性低拷贝重复序列（LCR22s）。由于大小、区域复杂性和单倍型多样性的综合影响，该区域的结构一直难以描述。为了使问题进一步复杂化，它在人类参考基因组中没有很好的体现。大多数 22q11.2 缺失综合征（22q11.2DS）患者携带一个约 3 Mbp 大小的从头发生的、半合子缺失，通过 LCR22s 介导的非等位基因同源重组（NAHR）发生。全面描绘个体 22q11.2 区域结构的能力对于评估未受影响个体在生殖细胞中产生重排的风险可能非常重要，这可能导致 22q11.2DS 的后代。为了了解这些风险因素，光学图谱先前已被用于成功阐明受 22q11.2DS 影响的 30 个家庭的 LCR22s 的结构和变异。其中一个家庭的父亲携带 t(11;22)(q23;q11)易位。令人惊讶的是，确定他是缺失起源的父系。NAHR 发生在他的 der(22)和完整的染色体 22 之间，导致他受影响的孩子出现 22q11.2 缺失。先证者的未受影响的兄弟姐妹继承了父亲的正常染色体 22，该染色体没有异常重组。这一意外观察结果明确表明，参与 NAHR 的单倍型也可以完整遗传。这项研究首次确定了所有涉及重排染色体 22 的结构，这些结构也参与了导致 22q11.2 缺失的 NAHR。
