The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.
The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.
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DOI：
10.1038/s41598-023-42202-1
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发表时间：
2023-12-06
影响因子：
4.6
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外显子组测序 (ES) 已用于多种临床环境，但其用于诊断和/或预测单基因肝病的实用性数据有限。我们制定了一份包含 502 个与肝脏表型相关的单基因疾病基因的精选列表，并分析了 758 名慢性肝病 (CLD) 患者中这些基因的 ES 数据。为了进行比较，我们检查了 7856 名自称健康对照 (HC) 和 2187 名慢性肾病 (CKD) 患者的 ES 数据。最初在 19.9% 的参与者中发现了候选致病 (P) 或可能致病 (LP) 变异，其中大部分归因于之前报道的等位基因频率高得令人难以置信的致病变异。根据群体次要等位基因频率进行变异注释和过滤（对于显性疾病，MAF ≤ 10–4，对于隐性疾病，MAF ≤ 10–3），我们检测到与 HC 队列相比，CLD 队列中 P/LP 变异显着富集（X2 检验 OR 5.00，95% CI 3.06–8.18，p 值 = 4.5e−12）。需要二级手动注释来捕获通过严格的等位基因频率和质量过滤器去除的真正致病变异。经过这些连续步骤后，CLD 队列中单基因疾病的诊断率为 5.7%，归因于 25 个基因中的 P/LP 变异。我们还确定了 15/22 具有肝脏基因 P/LP 变异的肾脏疾病患者的一致肝脏疾病表型，主要与囊性肝病表型相关。测序结果对临床管理有许多影响，包括早期诊断和管理的家族检测、相关合并症的预防性筛查，以及在某些情况下的治疗。外显子组测序对 CLD 患者的诊断率为 5.7%，需要进行多轮审查以减少假阳性和假阴性结果。在许多患有 P/LP 变异且无已知肝脏疾病的患者中鉴定出一致的表型，也表明对选定的单基因肝脏疾病进行预测测试的潜力。
Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10–4 for dominant disorders and MAF ≤ 10–3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06–8.18, p value = 4.5e−12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.
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DOI：
10.1056/nejmsr1809937
发表时间：
2019-08-15
期刊：
The New England journal of medicine
影响因子：
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作者：
All of Us Research Program Investigators;Denny JC;Rutter JL;Goldstein DB;Philippakis A;Smoller JW;Jenkins G;Dishman E
通讯作者：
Dishman E
影响因子：
14.9
作者：
Köhler S;Vasilevsky NA;Engelstad M;Foster E;McMurry J;Aymé S;Baynam G;Bello SM;Boerkoel CF;Boycott KM;Brudno M;Buske OJ;Chinnery PF;Cipriani V;Connell LE;Dawkins HJ;DeMare LE;Devereau AD;de Vries BB;Firth HV;Freson K;Greene D;Hamosh A;Helbig I;Hum C;Jähn JA;James R;Krause R;F Laulederkind SJ;Lochmüller H;Lyon GJ;Ogishima S;Olry A;Ouwehand WH;Pontikos N;Rath A;Schaefer F;Scott RH;Segal M;Sergouniotis PI;Sever R;Smith CL;Straub V;Thompson R;Turner C;Turro E;Veltman MW;Vulliamy T;Yu J;von Ziegenweidt J;Zankl A;Züchner S;Zemojtel T;Jacobsen JO;Groza T;Smedley D;Mungall CJ;Haendel M;Robinson PN
通讯作者：
Robinson PN
影响因子：
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作者：
Li, Xin-Hua;Lu, Yi;Zhang, Xin-Xin
通讯作者：
Zhang, Xin-Xin
RINT1 双等位基因变异导致婴儿期复发性急性肝衰竭和骨骼异常。
影响因子：
9.8
作者：
Cousin, Margot A.;Conboy, Erin;Klee, Eric W.
通讯作者：
Klee, Eric W.
DOI：
10.15585/mmwr.mm6638a9
发表时间：
2017-09-29
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
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作者：
通讯作者：
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