Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.
Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.
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DOI：
10.1186/s13073-022-01113-y
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发表时间：
2022-09-30
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
在医学遗传学中，疾病性状贡献基因和等位基因的发现和表征取决于遗传推理、研究设计和患者确定；我们建议采用分段单倍体遗传学方法来增强基因发现和分子诊断。我们构建了非等位同源重组 (NAHR) 介导的复发性基因组缺失的全基因组图谱，并使用该图谱根据大规模人群队列和区域特定研究来估计 NAHR 缺失的人群频率。我们使用 ClinVar 和 gnomAD 的高质量致病或可能致病变异计算了隐性疾病携带者负担。我们通过量化 NAHR 缺失对总等位基因负荷的贡献（列举了致病等位基因的所有成对组合），制定了隐性疾病 NIRD（NAHR 缺失对隐性疾病的影响）评分；我们使用基于随机交配假设的旁尼特方方法。进行文献挖掘，以识别所有报告的具有高 NIRD 评分基因缺陷的患者；对这些患者进行荟萃分析，以估计当代人类基因组学研究中隐性特征中 NAHR 缺失的表现。对现有临床外显子组测序 (cES) 进行回顾性分析，以发现 NAHR 缺失个体的新型罕见隐性疾病性状基因和等位基因。我们提出了关于 NAHR 复发性节段变异对隐性疾病负担的全基因组影响的新的基因组见解；我们证明了 NAHR 重复缺失的实用性，可以在常染色体隐性 (AR) 性状和双等位变异的挑战性背景下增强发现。计算结果表明，由 NAHR 介导的新突变涉及 30 个基因组区域的反复缺失，可能会导致这些片段缺失内超过 74% 的基因座或全基因组基因座中至少 2% 的隐性疾病负担。对 170 名文献报道的患者进行的荟萃分析表明，NAHR 缺失已从确定的 AR 性状等位基因库中耗尽。对含有反复缺失的受试者的个人基因组进行外显子组再分析，发现了导致疾病的新基因变异，包括 COX10、ERCC6、PRRT2 和 OTUD7A。我们的结果表明，对具有 NAHR 缺失的个人基因组进行基因组测序可以显着改善等位基因和基因发现，并增强临床分子诊断。此外，结果表明 NAHR 事件可能使人类单倍体遗传筛选成为疾病生物学实验研究的一种方法。在线版本包含可在 10.1186/s13073-022-01113-y 获取的补充材料。
In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics. We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions. We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A. Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology. The online version contains supplementary material available at 10.1186/s13073-022-01113-y.
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影响因子：
4
作者：
Dennis MY;Eichler EE
通讯作者：
Eichler EE
影响因子：
4
作者：
Ben-Shachar S;Lanpher B;German JR;Qasaymeh M;Potocki L;Nagamani SC;Franco LM;Malphrus A;Bottenfield GW;Spence JE;Amato S;Rousseau JA;Moghaddam B;Skinner C;Skinner SA;Bernes S;Armstrong N;Shinawi M;Stankiewicz P;Patel A;Cheung SW;Lupski JR;Beaudet AL;Sahoo T
通讯作者：
Sahoo T
影响因子：
9.8
作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
通讯作者：
Carvalho, Claudia M. B.
DOI：
10.1073/pnas.95.17.9985
发表时间：
1998-08-18
影响因子：
11.1
作者：
Coleman, MP;Conforti, L;Perry, VH
通讯作者：
Perry, VH
影响因子：
30.8
作者：
Chen, Wan-Jin;Lin, Yu;Wu, Zhi-Ying
通讯作者：
Wu, Zhi-Ying