Identification of novel candidate disease genes from de novo exonic copy number variants.
Identification of novel candidate disease genes from de novo exonic copy number variants.
复制标题
DOI：
10.1186/s13073-017-0472-7
复制
发表时间：
2017-09-21
期刊：
影响因子：
12.3
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Gambin T;Yuan B;Bi W;Liu P;Rosenfeld JA;Coban-Akdemir Z;Pursley AN;Nagamani SCS;Marom R;Golla S;Dengle L;Petrie HG;Matalon R;Emrick L;Proud MB;Treadwell-Deering D;Chao HT;Koillinen H;Brown C;Urraca N;Mostafavi R;Bernes S;Roeder ER;Nugent KM;Bader PI;Bellus G;Cummings M;Northrup H;Ashfaq M;Westman R;Wildin R;Beck AE;Immken L;Elton L;Varghese S;Buchanan E;Faivre L;Lefebvre M;Schaaf CP;Walkiewicz M;Yang Y;Kang SL;Lalani SR;Bacino CA;Beaudet AL;Breman AM;Smith JL;Cheung SW;Lupski JR;Patel A;Shaw CA;Stankiewicz P
外显子靶向微阵列可以检测小的（<1000 bp）基因内拷贝数变异（CNVs），包括那些仅影响单个外显子的变异。这种全基因组高灵敏度方法增加了已知疾病相关基因条件的分子诊断，实现了更好的基因型-表型相关性，并促进了变异等位基因检测，从而发现了新的疾病基因。我们回顾性分析了2007年至2017年贝勒遗传学实验室63,127例临床染色体微阵列分析（CMA）患者的数据，其中包括46,755例使用外显子靶向阵列进行测试的患者。发现了含有单个基因或两到五个非疾病相关基因的小CNVs；对涉及的基因进行了潜在疾病关联评估。在该临床人群中，在7200例患者（11%）报告的涉及任何单一基因的罕见CNVs中，我们发现145个新生常染色体CNVs（117个缺失，28个基因内获得），257个男性x连锁缺失CNVs， 1049个遗传常染色体CNVs（878个缺失，171个基因内获得）；111个已知的疾病基因可能被新生常染色体或x连锁（男性）单基因CNVs破坏。91个基因，无论是最近提出的候选疾病基因还是尚未与疾病相关的基因，被147个单基因cnv破坏，包括37个常染色体上的新生缺失和10个新生基因内复制，以及100个雄性x连锁cnv。将包含最多5个基因（224 bp至1.6 Mb）的新生或x连锁CNVs个体的临床特征与内部CMA数据库中较大缺失（大小达5 Mb）或临床或研究用全外显子组测序（WES）检测到的功能缺失单核苷酸变异（snv）个体的临床特征进行了比较。这使得鉴定出最近发表的基因（BPTF、NONO、PSMD12、TANGO2和TRIP12），新的候选疾病基因（ARGLU1和STK3），并进一步确认了两个最近提出的疾病基因（MEIS2和PTCHD1）的疾病相关性。值得注意的是，外显子靶向CMA检测到临床WES分析遗漏的几种致病性单外显子CNVs。总之，这些数据证明了外显子靶向CMA检测基因和外显子CNVs的有效性，补充和扩展了WES在临床诊断中的应用，以及通过全基因组分析发现新疾病基因的潜力。本文的在线版本（doi:10.1186/ s130773 -017-0472-7）包含补充材料，可供授权用户使用。
Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype–phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay. The online version of this article (doi:10.1186/s13073-017-0472-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2
作者：
Dworschak, Gabriel C.;Draaken, Markus;Reutter, Heiko
通讯作者：
Reutter, Heiko
影响因子：
8.8
作者：
Aradhya, Swaroop;Lewis, Rachel;Suchy, Sharon
通讯作者：
Suchy, Sharon
影响因子：
4.6
作者：
Bayer, D. K.;Martinez, C. A.;Stray-Pedersen, A.
通讯作者：
Stray-Pedersen, A.
影响因子：
8.8
作者：
Cheung, SW;Shaw, CA;Beaudet, AL
通讯作者：
Beaudet, AL