BACKGROUND Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. METHODS To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. RESULTS We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. CONCLUSIONS In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.

中文翻译：

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通过外显子组测序检测的致病基因中的马赛克单核苷酸变异体的临床调查。

背景技术尽管几十年来已知马赛克变异体引起疾病，但是具有分析灵敏度以在减少的等位基因片段上一致地检测变异体的高通量测序技术直到最近才作为常规临床诊断测试出现。迄今为止，已经很少通过诊断性外显子组测序对多种临床指征检测到的镶嵌变异进行系统的分析。方法为了研究临床相关的体细胞镶嵌单核苷酸变体（SNV）的频率，类型，等位基因分数和表型后果以及相应基因的特征，我们回顾性地从约12,000个样本中报告了镶嵌变异体，这些样本已提交临床外显子组测序。 （ES）来自Baylor Genetics。结果我们发现了120个涉及107个基因的镶嵌变异，在先证者样本中包括80个镶嵌SNV，在父母/祖父母样本中包括40个。女性的常染色体和X连锁疾病基因中检测到的平均镶嵌替代等位基因分数（AAF）为18.2％，而男性的X连锁疾病基因中为34.8％。在这些镶嵌变体中，有74个变种（61.7％）被归为致病或可能致病物种，有46个变种（38.3％）被归为不确定意义的变种。在常染色体显性遗传（AD）或AD /常染色体隐性遗传（AR）（67/120，55.8％），X连锁（33/120，27.5％），AD /体细胞（10/120， 8.3％）和AR（8/120，6.7％）继承。值得注意的是，在仅描述了体细胞事件的基因中发现了1.7％（2/120）的变体。九个基因在无关的个体中有复发性镶嵌事件，占18。在这项研究中，所有检测到的镶嵌变体中有3％（22/120）。先证者组丰富了影响Ras信号通路基因的镶嵌作用。结论总之，在该队列中进行的所有分子诊断中，估计有1.5％归因于先证者中检测到的镶嵌变异，而在0.3％的分析家庭中发现了亲本镶嵌。由于ES设计偏爱覆盖范围广而不是覆盖深度，因此镶嵌变异体患病率的这一估计很可能低估了我们队列中临床相关镶嵌变异体的总数。而在所分析的家庭中，有0.3％的人发现了亲本镶嵌。由于ES设计偏爱覆盖范围广而不是覆盖深度，因此镶嵌变异体患病率的这一估计可能低估了我们队列中临床相关镶嵌变异体的总数。而在所分析的家庭中，有0.3％的人确定了父母的马赛克。由于ES设计偏爱覆盖范围广而不是覆盖深度，因此镶嵌变异体患病率的这一估计可能低估了我们队列中临床相关镶嵌变异体的总数。