这 大规模外显子组测序作为单基因孟德尔疾病基因诊断中最具成本效益的策略，其自身设计存在局限性：它不包括内含子区域的测序。现在可以对整个基因组进行大规模测序，但尽管如此，处理该技术获得的信息所需的生物信息学技术和科学积累还不够成熟，不足以用于日常临床实践。这就是为什么我们必须意识到某些疾病可以通过外显子组测序未检测到的深层内含子变异来解释的可能性。
这对于隐性疾病特别重要，如果在一个等位基因中检测到致病性变异，但在另一个等位基因中未检测到致病性变异，或者在表型高度提示该疾病的情况下，考虑到复合杂合性的可能性，则必须考虑这一点。
拼接。
内含子变异对表型产生影响的机制主要与剪接有关。
基因组中内含子的存在是真核细胞的特征性生物学现象，其具有的主要进化优势是能够选择不同的外显子组合，从而增加了基因表达的多样性。我们从 RNA 前体序列（DNA 的精确拷贝）获得没有内含子的 mRNA 序列的过程称为剪接。负责此功能的核糖核蛋白机制被称为 剪接体.
主要有2种，即主要剪接体和次要剪接体。它是一种由多种机制调节的机器，包括激活器（增强器）和消音器（消音器）。这些调制器的作用引起了一种称为 选择性剪接，因此同一基因可以根据情况产生不同的蛋白质产物。根据目前的估计，大约 15-50% 的致病单基因点突变会影响 RNA 前体剪接，其中大多数影响剪接点。
内含子突变的致病机制。
- 包含伪外显子。
- 与自然剪接位点的竞争。
- 转录调控元件的破坏。
- 非编码 RNA 失活。
- 染色体重排。
文献中描述的具有致病性内含子突变的疾病。
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1.
Vaz-Drago R、Custódio N、Carmo-Fonseca M。深度内含子突变与人类疾病。嗡嗡声热内特[互联网]。 2017 年[引用于 2020 年 5 月 3 日]；136(9):1093–111。可从： http://link.springer.com/10.1007/s00439-017-1809-4
1.
Anna A，Monika G。人类遗传疾病中的剪接突变：示例、检测和确认。应用遗传学杂志[互联网]。 2018 年[引用于 2021 年 7 月 12 日]；59(3):253–68。可从： http://link.springer.com/10.1007/s13353-018-0444-7