Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.
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对1000个遗传性视网膜疾病的连续家庭进行临床焦点分子研究。
DOI：
10.1016/j.ophtha.2017.04.008
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发表时间：
2017-09
期刊：
影响因子：
13.7
通讯作者：
Tucker BA
中科院分区：
文献类型：
--
作者：
Stone EM;Andorf JL;Whitmore SS;DeLuca AP;Giacalone JC;Streb LM;Braun TA;Mullins RF;Scheetz TE;Sheffield VC;Tucker BA
为遗传性视网膜疾病设计一种全面的多平台基因检测策略，并描述其在由一名临床医生观察的1,000个连续家庭中的表现。回顾了2010年1月至2016年6月期间由一名视网膜专家就诊的所有患者的临床记录，所有符合遗传性视网膜疾病诊断临床标准的患者均被纳入研究。每例患者被分配到62个诊断类别中的一个，该临床诊断用于定义所进行的分子研究的范围和顺序。在给定的受试者中评估的核苷酸数量范围从2个（针对BBS 1和BBS 10中最常见突变的多重等位基因特异性测定）到近900，000个（已知引起遗传性视网膜疾病的305个基因的编码序列和剪接点）。致病基因型在760个家庭（76%）。这些基因型分布在104个不同的基因中。这104个基因中超过70%的编码序列足够小，可以有效地包装到腺相关病毒中。ABCA 4突变是该队列（173个家庭）中最常见的疾病原因，而80个基因的突变导致5个或更少家庭的疾病（即，0.5%或更低）。在576个没有下一代测序（NGS）的家庭中确定了致病基因型。这包括23个在RPGR外显子15的重复区域发生突变的家庭，这些突变可能会被NGS遗漏。其余424个家庭的全外显子组测序显示了另外182个家庭的突变，其余242个家庭中的4个家庭的全基因组测序显示了其他方法无法看到的另外两种基因型。以临床为重点的分层方式进行检测将比使用全外显子组测序评估所有患者中超过300个基因的平均假基因型率高6.1%，低17.7%，并且具有显著更低的平均假基因型率（7.1 vs. 128%; p<0.001）。遗传性视网膜疾病的基因检测现在敏感性超过75%。临床导向的分层测试策略可以在不增加成本的情况下提高灵敏度并改善统计学显著性。
To devise a comprehensive multi-platform genetic testing strategy for inherited retinal disease and describe its performance in 1,000 consecutive families seen by a single clinician. The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to one of 62 diagnostic categories and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from two (a multiplex allele-specific assay for the most common mutations in BBS1 and BBS10) to nearly 900,000 (the coding sequences, and splice junctions of 305 genes known to cause inherited retinal disease). Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 70% of these 104 genes have coding sequences small enough to be efficiently packaged into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families) while mutations in 80 genes caused disease in five or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole exome sequencing of the remaining 424 families revealed mutations in an additional 182, and whole genome sequencing of four of the remaining 242 families revealed two additional genotypes that were invisible by the other methods. Performing the testing in a clinically-focused tiered fashion would be 6.1% more sensitive, 17.7% less expensive and have a significantly lower average false genotype rate than using whole exome sequencing to assess more than 300 genes in all patients (7.1 vs. 128%; p<0.001). Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically-directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost.
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影响因子：
3.5
作者：
Braun TA;Mullins RF;Wagner AH;Andorf JL;Johnston RM;Bakall BB;Deluca AP;Fishman GA;Lam BL;Weleber RG;Cideciyan AV;Jacobson SG;Sheffield VC;Tucker BA;Stone EM
通讯作者：
Stone EM
影响因子：
4.6
作者：
Kansakoski, Johanna;Jaaskelainen, Jarmo;Raivio, Taneli
通讯作者：
Raivio, Taneli
影响因子：
56.9
作者：
KAJIWARA, K;BERSON, EL;DRYJA, TP
通讯作者：
DRYJA, TP
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1126/science.1232033
发表时间：
2013-02-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mali P;Yang L;Esvelt KM;Aach J;Guell M;DiCarlo JE;Norville JE;Church GM
通讯作者：
Church GM