The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation.
The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation.
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DOI：
10.1186/s13073-022-01123-w
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发表时间：
2022-10-27
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
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多个从头拷贝数变异（MdnCNV）表型被描述为具有四个或更多个组成性从头CNV（dnCNV），其在一代内独立地出现在整个人类基因组中。这是一种罕见的围合子突变事件，以前报道每12，000名因先天性异常而进行全基因组染色体微阵列分析的个体中就有一次。这些罕见的家庭提供了一个独特的机会，了解围合子基因组不稳定性的遗传因素和dnCNV对人类疾病的影响。对新鉴定的MdnCNV家族进行染色体微阵列分析（CMA）、基于阵列的比较基因组杂交、短读和长读基因组测序（GS），以鉴定包括dnCNV、从头单核苷酸变体（dnSNV）和插入缺失的从头突变。对四个先前发表的MdnCNV家族进行短读GS用于dnSNV分析。对新鉴定的个体和4个先前发表的MdnCNV家族进行基于Trio的罕见变异分析，以鉴定导致围合子基因组不稳定性的潜在遗传病因。Lin语义相似性评分告知对三个MdnCNV家族的定量人类表型本体分析，以鉴定驱动或促成临床表型的基因。在新发现的MdnCNV病例中，我们发现了8个从头串联重复，每个约1 Mb，在6/8个断点连接处具有微同源性。在dnCNV基因组区域的4 Mb内发现了从头单核苷酸变体（SNV; 6/79）和从头indel（1/12）的富集。在MdnCNV家族中观察到合子后SNV突变率升高。母亲罕见变异分析确定了三个基因在不同的家庭，可能有助于MdnCNV现象。表型分析表明，在3/3例病例中，dnCNV区域内的基因有助于观察到的先证者表型。在两种情况下，CNV，包括PMP 22和RAI 1的连续基因重复和影响NSD 1和SMARCC 2的另一个重复，有助于临床观察到的表型表现。dnCNVs的特征性特征与围合子期微同源介导的断裂诱导复制（MMBIR）驱动机制一致。DNA修复基因中的母体遗传变异可能导致合子周基因组不稳定性。在三个MdnCNV先证者的队列中观察到可变的表型特征，计算定量表型分析显示，三分之二的人有证据表明一个以上的遗传位点对先证者的表型的贡献，支持这些家族中从头多位点致病变异（MPV）的假设。在线版本包含补充材料，可通过10.1186/s13073-022-01123-w获得。
The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases. Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified MdnCNV family to identify de novo mutations including dnCNVs, de novo single-nucleotide variants (dnSNVs), and indels. Short-read GS was performed on four previously published MdnCNV families for dnSNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published MdnCNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three MdnCNV families to identify gene(s) driving or contributing to the clinical phenotype. In the newly identified MdnCNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dnCNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in MdnCNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the MdnCNV phenomenon. Phenotype analysis suggests that gene(s) within dnCNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2, contribute to the clinically observed phenotypic manifestations. Characteristic features of dnCNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three MdnCNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband’s phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families. The online version contains supplementary material available at 10.1186/s13073-022-01123-w.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
DOI：
10.1093/bioinformatics/btx346
发表时间：
2017-10-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Serra E
通讯作者：
Serra E
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
COULONDRE, C;MILLER, JH;GILBERT, W
通讯作者：
GILBERT, W
影响因子：
8.8
作者：
Cheung, SW;Shaw, CA;Beaudet, AL
通讯作者：
Beaudet, AL