The Promise and Peril of Precision Medicine: Phenotyping Still Matters Most
The Promise and Peril of Precision Medicine: Phenotyping Still Matters Most
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DOI：
10.1016/j.mayocp.2016.08.008
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发表时间：
2016-11-01
影响因子：
8.9
通讯作者：
Ackerman, Michael J.
中科院分区：
文献类型：
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作者：
Ackerman, Jaeger P.;Bartos, Daniel C.;Ackerman, Michael J.
我们说明了必要的工作，以扭转过程后，错误地解释为导致长QT综合征（LQTS）的KCNQ 1变异识别和确定的真正原因的情况下，猝死的年轻人。对死者在世兄弟的替代基因检测发现了一种罕见的KCNQ 1-V133 I变体，这促使植入式心律转复除颤器，并随后在其他家庭成员中诊断出LQTS。随后，这个假定的LQT 1家族来到我们的机构进行进一步的临床评估和基于研究的调查，包括死者的KCNQ 1-V133 I变体特异性分析，KCNQ 1-V133 I的异源表达研究，以及全外显子组分子解剖沿着使用其未受影响的父母的DNA的基因组三角测量。在评估了几个V133 I阳性的家族成员后，临床上对以前诊断LQT 1的准确性产生了怀疑，导致重新开放病例并对致命底物进行了激烈的追求。此外，对V133 I检测为阴性，并且异源表达研究证明了含V133 I的Kv7.1通道的正常细胞表型。相反，在全外显子组分子尸检后，在DES编码的结蛋白中鉴定了一种从头致病性变体（p.R454W）。如本文所述，对年轻人猝死的法医评估需要对死者进行细致的关注，然后对死者的亲属进行仔细和慎重的评估。替代基因检测可能会产生灾难性的后果，应该避免。基因检测结果需要仔细审查，以避免意外和潜在的破坏性影响。虽然死者悲惨死亡的根本原因仍然是一个谜，但仅基于临床理由，本文所述的对在世亲属的意外后果可能已经避免。所有家族成员的心电图QT间期均正常，不太可能诊断为家族性LQTS。因此，如果照顾这些患者的临床医生只关注幸存者的临床数据，那么就没有理由走上基于基因检测的不适当治疗之路。(C)2016年马约医学教育和研究基金会
We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variantespecific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing. (C) 2016 Mayo Foundation for Medical Education and Research