Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements.

结构性镶嵌异常是存在于细胞亚群中的大的合子后突变，并与发育障碍和癌症有关。此类突变已通过细胞遗传学或微阵列测试在临床诊断中进行了常规评估。现代疾病研究严重依赖外显子组测序，但是缺乏使用靶向测序数据检测结构嵌合体的适当方法。在这里，我们提出了一种名为MrMosaic的方法，该方法使用等位基因分数的偏差来检测结构性镶嵌异常，并从下一代测序数据中读取覆盖率。使用全外显子测序（WES）和全基因组测序（WGS）模拟来计算一系列镶嵌事件大小，类型，克隆性和测序深度的检测性能。该工具用于4911例未确诊的发育障碍患者，在9例患者中检测到11个事件。在这11个事件中的8个中，在唾液中观察到镶嵌现象，但在血液中未观察到镶嵌现象，这表明仅检测血液会遗漏镶嵌诊断染色体重排的很大一部分，可能> 50％。