Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.
Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.
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基因组测序提高了临床诊断为阿拉杰尔综合征但先前检测结果为阴性的患者的诊断率。
DOI：
10.1038/s41436-020-00989-8
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Spinner NB
中科院分区：
文献类型：
--
作者：
Rajagopalan R;Gilbert MA;McEldrew DA;Nassur JA;Loomes KM;Piccoli DA;Krantz ID;Conlin LK;Spinner NB
在一次检测中检测所有主要类别的基因组变异将降低成本并提高基因组诊断的效率。基因组测序（GS）有可能提供这种全面的检测水平。我们试图证明GS在18例临床确诊为阿拉杰里综合征（ALGS）患者的分子诊断中的效用，这些患者通过标准护理检测得到阴性或不确定的结果。
我们对16例致病变异阴性先证者和2例结果不确定的先证者（共406例ALGS先证者）进行了GS，并分析了JAG1和NOTCH2中的序列、拷贝数和结构变异数据。
GS鉴定出4种新的致病性改变，包括JAG1中的拷贝数中性倒位、部分缺失和启动子变异，以及NOTCH2的部分缺失，额外诊断率为0.9%。此外，GS解析了两种复杂的重排，导致在GS后97.5%（n = 396/406）的患者中鉴定出致病变异。
对于那些先前通过其他方法进行基因检测为阴性或不完整的临床确诊为ALGS的个体，GS提高了诊断率。我们的结果表明，GS能够检测所有主要类别的变异，并有可能成为孟德尔疾病的单一一线诊断测试。
Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing. We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2. GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS. GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.
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影响因子：
9.2
作者：
Pedersen, Brent S.;Collins, Ryan L.;Quinlan, Aaron R.
通讯作者：
Quinlan, Aaron R.
影响因子：
4
作者：
Ansari M;Poke G;Ferry Q;Williamson K;Aldridge R;Meynert AM;Bengani H;Chan CY;Kayserili H;Avci S;Hennekam RC;Lampe AK;Redeker E;Homfray T;Ross A;Falkenberg Smeland M;Mansour S;Parker MJ;Cook JA;Splitt M;Fisher RB;Fryer A;Magee AC;Wilkie A;Barnicoat A;Brady AF;Cooper NS;Mercer C;Deshpande C;Bennett CP;Pilz DT;Ruddy D;Cilliers D;Johnson DS;Josifova D;Rosser E;Thompson EM;Wakeling E;Kinning E;Stewart F;Flinter F;Girisha KM;Cox H;Firth HV;Kingston H;Wee JS;Hurst JA;Clayton-Smith J;Tolmie J;Vogt J;Tatton-Brown K;Chandler K;Prescott K;Wilson L;Behnam M;McEntagart M;Davidson R;Lynch SA;Sisodiya S;Mehta SG;McKee SA;Mohammed S;Holden S;Park SM;Holder SE;Harrison V;McConnell V;Lam WK;Green AJ;Donnai D;Bitner-Glindzicz M;Donnelly DE;Nellåker C;Taylor MS;FitzPatrick DR
通讯作者：
FitzPatrick DR
DOI：
10.1007/978-3-319-65109-5_3
发表时间：
2018-01-01
期刊：
TWENTY-FIRST CENTURY MARIANNE MOORE: ESSAYS FROM A CRITICAL RENAISSANCE
影响因子：
--
作者：
Gilbert, Roger
通讯作者：
Gilbert, Roger
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
4
作者：
Kamath BM;Bauer RC;Loomes KM;Chao G;Gerfen J;Hutchinson A;Hardikar W;Hirschfield G;Jara P;Krantz ID;Lapunzina P;Leonard L;Ling S;Ng VL;Hoang PL;Piccoli DA;Spinner NB
通讯作者：
Spinner NB