Unrecognized scale and clinical relevance of somatic mosaicism

体细胞嵌合体的规模和临床相关性未被认识

• 批准号: 10011833
• 负责人: PAWEL STANKIEWICZ
• 金额: $ 50.45万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011833
• 关键词: Affect; Algorithms; Biological Assay; Blood; Blood Tests; Cell division; Cells; Child; Clinical; Clinical Research; Constitutional; Copy Number Polymorphism; Counseling; DNA; DNA biosynthesis; Data; Databases; Detection; Development; Diagnosis; Disease; Drug or chemical Tissue Distribution; Embryonic Development; Etiology; Event; Evolution; Family; Fathers; Fibroblasts; Fostering; Frequencies; Gametogenesis; Generations; Genetic; Genetic Counseling; Genetic Diseases; Genetic Materials; Genetic Research; Genome; Genomics; Germ Cells; Guidelines; Hair follicle structure; Health; Heritability; Human; Individual; Inherited; Measures; Mediating; Meiosis; Mendelian disorder; Methods; Microarray Analysis; Mitosis; Mitotic; Molecular; Mosaicism; Mutagenesis; Mutation; Nonhomologous DNA End Joining; Oral mucous membrane structure; Organism; Parents; Pathogenicity; Patients; Penetrance; Plasma; Population Study; Pregnant Women; Prenatal Diagnosis; Prevalence; Procedures; Process; Publishing; Recurrence; Replication Error; Resolution; Risk; Saliva; Sampling; Sensitivity and Specificity; Single Nucleotide Polymorphism; Skin; Somatic Mutation; Structure; Technology; Testing; Tissue Sample; Tissues; Urine; Variant; Work; base; clinical diagnostics; clinically relevant; design; exome sequencing; expectation; fetal; genetic testing; genome sequencing; genome-wide; homologous recombination; human tissue; insertion/deletion mutation; insight; intergenerational; molecular sequence database; next generation; next generation sequencing; offspring; patient population; prenatal testing; screening; sperm cell; whole genome

ABSTRACT Nearly all of the genetic material among cells within an organism is identical. However, single-nucleotide variants (SNVs), copy-number variants (CNVs), and other structural variants continually accumulate as cells divide during development. This process results in an organism composed of countless cells, each with its own unique genome. Thus, every human is undoubtedly mosaic. Mosaic mutations can go unnoticed, underlie genetic disease or normal human variation, and may be transmitted to the next generation as constitutional variants and cause unexpected intergenerational recurrences of genetic disorders with multiple affected children born to unaffected parents, contrary to Mendelian expectations. The increasing sensitivity and resolution of genomic technologies have identified mosaicism for both SNVs and CNVs. Combined somatic and germline mosaicism has been identified in parents of patients with a number of genetic conditions, thus raising the possibility that mosaic individuals might be detected by routine blood tests rather than requiring direct examination of germ cells. Yet despite its considerable impact on human health, systematic population studies of both germline and somatic mosaicism are lacking. In contrast to recurrent CNVs, usually mediated by nonallelic homologous recombination during meiosis, nonrecurrent CNVs are thought to arise due to DNA replication errors, such as microhomology-mediated break-induced replication during mitosis or non- homologous end joining. Recurrence risks of putatively de novo nonrecurrent CNVs designed to take into account random chance and mosaicism have been previously estimated to be ~ 0.3%. Our preliminary published data on 100 unrelated affected families indicate that somatic mosaicism for CNVs is present in ~ 4% of healthy parents. Currently, the detection rates for CMA and WES are ~ 20% and ~ 25%, respectively, thus in about half of patients no pathogenic variant is found. We propose that some of these patients may have mosaic pathogenic variants that are currently undetected using standard algorithms in CMA and WES. Unrecognized mosaicism could also partially explain variable expressivity and incomplete penetrance. We hypothesize that a significant number of apparently de novo SNVs and CNVs are not meiotic in origin but arise during early post-zygotic mitoses and this can be identified either in the affected patients or their healthy parents. In Aims 1 and 2, we will search for low-level somatic mosaicism in reportedly healthy parents of 500 affected children who have apparent de novo CNVs, indels, or SNVs identified in their affected children. In Aim 2, we will develop a non-invasive prenatal test for detection of recurrent mutations and correlate sperm vs. somatic mosaicism. In Aim 3, we will study somatic mosaic CNVs, indels, and SNVs in patients in whom no nonmosaic pathogenic variant has been found in previous clinical or research genetic testing. We will estimate the currently unrecognized and poorly understood prevalence and clinical consequences of somatic mosaicism and inform about molecular mechanisms of early post-zygotic mutagenesis and human evolution.

抽象的 生物体内细胞间几乎所有遗传物质都是相同的。然而，单核苷酸 变异（SNV）、拷贝数变异（CNV）和其他结构变异随着细胞不断积累 开发过程中的分裂。这个过程产生了由无数细胞组成的有机体，每个细胞都有自己的 独特的基因组。因此，每个人无疑都是马赛克。马赛克突变可能会被忽视，是其背后的原因 遗传性疾病或正常人类变异，并且可能作为体质遗传给下一代 变异并导致具有多种受影响的遗传性疾病的意外代际复发 与孟德尔的期望相反，未受影响的父母所生的孩子。日益增加的敏感性和 基因组技术的分辨率已经确定了 SNV 和 CNV 的嵌合现象。组合体细胞 在患有多种遗传疾病的患者的父母中已经发现了种系嵌合，因此 提高了通过常规血液检测而不是需要检测马赛克个体的可能性 直接检查生殖细胞。然而，尽管系统人口对人类健康影响相当大， 缺乏对种系嵌合体和体细胞嵌合体的研究。与复发性 CNV 相比，通常介导 通过减数分裂过程中的非等位同源重组，非复发性 CNV 被认为是由 DNA 引起的 复制错误，例如有丝分裂或非复制过程中微同源介导的断裂诱导的复制 同源末端连接。假定的从头非复发性 CNV 的复发风险旨在考虑 先前估计随机机会和镶嵌现象约为 0.3%。我们的初步 已发表的 100 个无关受影响家庭的数据表明，CNV 的体细胞嵌合存在于约 4% 的人中 健康的父母。目前，CMA 和 WES 的检出率分别为约 20% 和约 25%，因此 大约一半的患者没有发现致病变异。我们建议其中一些患者可能患有 目前使用 CMA 和 WES 中的标准算法无法检测到的嵌合致病变异。 未被识别的镶嵌现象也可以部分解释可变的表现力和不完全的外显率。我们 假设大量明显从头开始的 SNV 和 CNV 并非起源于减数分裂，而是出现的 在早期合子后有丝分裂期间，这可以在受影响的患者或其健康人中识别出来 父母。在目标 1 和 2 中，我们将在 500 名据报道健康的父母中寻找低水平的体细胞嵌合体 在受影响的儿童中发现明显的从头 CNV、插入缺失或 SNV。瞄准 2、我们将开发一种非侵入性产前测试，用于检测复发性突变并将精子与精子相关联。 体细胞嵌合体。在目标 3 中，我们将研究无症状患者的体细胞嵌合 CNV、插入缺失和 SNV。 非嵌合致病变异已在之前的临床或研究基因检测中发现。我们将估计 目前尚未认识到和知之甚少的体细胞嵌合体的患病率和临床后果 并了解早期合子后突变和人类进化的分子机制。