Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.
Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.
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DOI：
10.1016/j.gim.2021.09.017
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Yuan B
中科院分区：
文献类型：
--
作者：
Chen CA;Lattier J;Zhu W;Rosenfeld J;Wang L;Scott TM;Du H;Patel V;Dang A;Magoulas P;Streff H;Sebastian J;Svihovec S;Curry K;Delgado MR;Hanchard NA;Lalani S;Marom R;Madan-Khetarpal S;Saenz M;Dai H;Meng L;Xia F;Bi W;Liu P;Posey JE;Scott DA;Lupski JR;Eng CM;Xiao R;Yuan B
BRG1/BRM 相关因子 (BAF) 复合体是一种染色质重塑复合体，在基因调控中发挥着关键作用。编码 BAF 亚基的基因缺陷会导致 BAFo 病，这是一组具有广泛基因座和表型异质性的神经发育障碍。我们回顾性分析了 16,243 名转诊进行临床外显子组测序 (ES) 的患者的数据，重点关注 BAF 复合体。我们应用基因型优先的方法结合预测的基因限制来提出候选 BAF 病基因。我们鉴定出 127 名患者的 11 种已知 BAF 病基因携带致病性、可能致病性变异或临床意义未知的新生变异 (VUS)。其中包括 34 名患者，通过 ES 再分析，利用新的基因疾病证据 (N = 21) 或已知 BAF 病基因的变异重新分类 (N = 13) 进行分子诊断。我们还鉴定了四种候选 BAF 病基因的从头或预测的功能丧失变异：ACTL6A、BICRA（在本研究中与 BAF 病有关）、PBRM1 和 SMARCC1。我们报告了 ES 队列中 BAFopathies 的突变谱。对 ES 数据进行基因型驱动和基于通路的再分析，确定了 BAFo 病候选基因的新证据。有必要对其他患者进行进一步的机制和表型表征，以确认他们在人类疾病中的作用并描绘其相关的表型谱。
The BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex playing a critical role in gene regulation. Defects in the genes encoding the BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach combining predicted genic constraints to propose candidate BAFopathy genes. We identified 127 patients carrying pathogenic, likely pathogenic variants or de novo variants of unknown clinical significance (VUS) in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed through ES reanalysis with new gene-disease evidence (N= 21) or variant re-classifications in known BAFopathy genes (N=13). We also identified de novo or predicted loss-of-function variants in four candidate BAFopathy genes, ACTL6A, BICRA (implicated in BAFopathy during this study), PBRM1, and SMARCC1. We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and a pathway-based reanalysis of ES data identified new evidence for candidate genes for BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.
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影响因子：
30.8
作者：
Gratten, Jacob;Visscher, Peter M.;Wray, Naomi R.
通讯作者：
Wray, Naomi R.
影响因子：
14.5
作者：
Lessel, Davor;Gehbauer, Christina;Kubisch, Christian
通讯作者：
Kubisch, Christian
影响因子：
9.8
作者：
Dias C;Estruch SB;Graham SA;McRae J;Sawiak SJ;Hurst JA;Joss SK;Holder SE;Morton JE;Turner C;Thevenon J;Mellul K;Sánchez-Andrade G;Ibarra-Soria X;Deriziotis P;Santos RF;Lee SC;Faivre L;Kleefstra T;Liu P;Hurles ME;DDD Study;Fisher SE;Logan DW
通讯作者：
Logan DW
影响因子：
16.2
作者：
Furey CG;Choi J;Jin SC;Zeng X;Timberlake AT;Nelson-Williams C;Mansuri MS;Lu Q;Duran D;Panchagnula S;Allocco A;Karimy JK;Khanna A;Gaillard JR;DeSpenza T;Antwi P;Loring E;Butler WE;Smith ER;Warf BC;Strahle JM;Limbrick DD;Storm PB;Heuer G;Jackson EM;Iskandar BJ;Johnston JM;Tikhonova I;Castaldi C;López-Giráldez F;Bjornson RD;Knight JR;Bilguvar K;Mane S;Alper SL;Haider S;Guclu B;Bayri Y;Sahin Y;Apuzzo MLJ;Duncan CC;DiLuna ML;Günel M;Lifton RP;Kahle KT
通讯作者：
Kahle KT
影响因子：
5.3
作者：
Bramswig, Nuria C.;Caluseriu, O.;Wieczorek, D.
通讯作者：
Wieczorek, D.