High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.
High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.
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DOI：
10.1111/epi.12489
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发表时间：
2014-02
期刊：
影响因子：
5.6
通讯作者：
Goldman AM
中科院分区：
文献类型：
--
作者：
Klassen TL;Bomben VC;Patel A;Drabek J;Chen TT;Gu W;Zhang F;Chapman K;Lupski JR;Noebels JL;Goldman AM
癫痫猝死（SUDEP）风险基因的高级变异检测可以揭示广泛的上位性复杂性，提高癫痫相关死亡率的诊断准确性。然而，在SUDEP的分子尸检中，仅基于已建立的心律失常基因的诊断面板的灵敏度和临床效用是未知的。我们应用已建立的临床诊断面板，然后测序和高密度拷贝数变异（CNV）检测阵列的额外253个相关的离子通道亚基基因，以分析整体基因组变异的3岁的先证者与婴儿期严重肌阵挛性癫痫（SMEI）的SUDEP。我们发现了在神经心脏和呼吸控制途径中表达的基因中单核苷酸多态性和CNV的复杂组合，包括SCN 1A，KCNA1，RYR3和HTR2C。我们的研究结果表明，全面的高分辨率变异分析在评估个人相关的SUDEP风险的重要性。在这种情况下，SCN1A和KCNA1基因中的从头SNP和CNV的组合被怀疑是癫痫和过早死亡的主要风险因素。然而，考虑到其广泛的功能上位相互作用的整体生物学相关的变异复杂性，更准确地揭示了潜在的个人风险。
Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the three year old proband with severe myoclonic epilepsy of infancy (SMEI). We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neuro-cardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Our findings demonstrate the importance of comprehensive high resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo SNPs and CNVs in the SCN1A and KCNA1 genes respectively is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.
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影响因子：
64.5
作者：
Klassen T;Davis C;Goldman A;Burgess D;Chen T;Wheeler D;McPherson J;Bourquin T;Lewis L;Villasana D;Morgan M;Muzny D;Gibbs R;Noebels J
通讯作者：
Noebels J
影响因子：
4.1
作者：
Klassen, Tara L.;Drabek, Janice;Goldman, Alicia M.
通讯作者：
Goldman, Alicia M.
影响因子：
9.9
作者：
Johnson, J. N.;Hofman, N.;Ackerman, M. J.
通讯作者：
Ackerman, M. J.
影响因子：
5.5
作者：
Glasscock, Edward;Qian, Jing;Noebels, Jeffrey L.
通讯作者：
Noebels, Jeffrey L.
影响因子：
14.5
作者：
Harkin, Louise A.;McMahon, Jacinta M.;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.