Casey Ruth T, Ascher David B, Rattenberry Eleanor, Izatt Louise, Andrews Katrina A, Simpson Helen L, Challis Benjamen, Park Soo-Mi, Bulusu Venkata R, Lalloo Fiona, Pires Douglas E V, West Hannah, Clark Graeme R, Smith Philip S, Whitworth James, Papathomas Thomas G, Taniere Phillipe, Savisaar Rosina, Hurst Laurence D, Woodward Emma R, Maher Eamonn R
Department of Medical GeneticsUniversity of Cambridge and NIHR Cambridge Biomedical Research CentreCambridgeCB2 2QQUK.
Department of EndocrinologyUniversity of Cambridge and NIHR Cambridge Biomedical Research CentreAddenbrooke's HospitalCambridgeCB2 2QQUK.
Mol Genet Genomic Med. 2017 Mar 2;5(3):237-250. doi: 10.1002/mgg3.279. eCollection 2017 May.
To evaluate the role of germline mutation analysis by (1) comprehensive literature review, (2) description of novel germline mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.
A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions.
Literature review revealed reports of 17 different germline variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare missense variants present in a control data set (ESP6500) were also associated with impaired protein stability.
The clinical spectrum of -associated neoplasia differs from that of germline mutations in other SDH-subunits. The interpretation of the significance of novel missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management.
通过（1）全面的文献综述、（2）描述新的种系突变以及（3）对SDHA中错义替换进行计算机模拟结构预测分析，来评估种系突变分析的作用。
对英国分子遗传学实验室中鉴定出具有假定种系变异的患者的分子和临床特征进行了系统的文献综述和回顾性分析。为了评估错义变异的分子后果，构建了SDHA/B/C/D复合物的新型模型，并通过mCSM计算平台预测了文献中、我们英国的新队列以及另外32个“对照错义变异”中鉴定出的错义替换的结构效应。这些结构预测与肿瘤研究结果和其他生物信息学预测相关联。
文献综述揭示了来自45个家族的47名受影响个体中17种不同种系变异的报告。我们英国的系列研究又增加了15例先前未报告病例中的10种不同变异（8名患者中有7种新变异）。对11个候选种系错义突变的计算机模拟结构预测研究表明，大多数（63.7%）会使SDHA原体不稳定，并且对照数据集（ESP6500）中存在的大多数（78.1%）罕见错义变异也与蛋白质稳定性受损有关。
与相关肿瘤形成的临床谱不同于其他SDH亚基中的种系突变。解释新的错义替换的意义具有挑战性。我们建议在利用基因检测结果影响临床管理之前，应进行多项调查（如肿瘤研究、代谢组学分析）以辅助罕见错义变异的分类。
