2012国际卒中大会：全外显子测序用于家族性颅内动脉瘤基因变异评估
2012-02-06 陈蓉 医学论坛网
2012年国际卒中大会上，来自辛辛那提大学的学者率先将全外显子组测序用于家族性颅内动脉瘤基因变异体的评估，进行了CIDR研究。初步结果证实采用基因本体论（GO）通路分析和连锁分析区分目标变异体的优先次序，可能是确定动脉瘤形成和破裂出血相关基因变异的有效策略。进一步研究需提供更确凿的证据以证实该方法的有效性。 全外显
2012年国际卒中大会上，来自辛辛那提大学的学者率先将全外显子组测序用于家族性颅内动脉瘤基因变异体的评估，进行了CIDR研究。初步结果证实采用基因本体论（GO）通路分析和连锁分析区分目标变异体的优先次序，可能是确定动脉瘤形成和破裂出血相关基因变异的有效策略。进一步研究需提供更确凿的证据以证实该方法的有效性。
全外显子组测序是一种鉴别疾病相关罕见基因变异的新型方法。然而，筛减大量的变异基因以揭示出一个有用的候选基因困难重重，还必须考虑环境因素（吸烟）和罕见变异之间的关系。
研究在7个罹患家族性颅内动脉瘤（IA）的家庭中，纳入了32例受影响的个人进行全外显子组测序。其中，一个家庭包含了患IA或主动脉瘤的成员。对所有样品进行基因分型和测序（人全外显子试剂盒）。经过广泛的质量和生物过滤，采用GO通路分析和连锁分析在全外显子组中区分变异体的优先次序。目前的分析仅包括单核苷酸变体（SNV）。插入/缺失现正在分析中。
结果表明，在确定的103967个双等位基因SNV中，83％在应用质量过滤后犹存，如缺失位点频度、过量杂合子/纯合子和链偏向性。如果变异体是同义或非外显子，或者它们的等位基因频率> 3％，那么该变异体会被进一步排除，仅余原来双等位基因SNV 中的9%。如果家庭中至少有3个受影响成员有相同的变异体（常染色体显性遗传；杂合子）或2个变异体（常染色体隐性遗传；复合杂合子或纯合子），那么生物过滤会将该基因保留。在保留的537个基因的618 个SNV中，有19个基因的27个变异体在所选择的GO类别中被发现，有10基因的12个变异体在1MB标签单核苷酸多态性（tag SNP）之内，检测极限（LOD）值> 1.15。仅有一个基因LAMA5（层粘连蛋白）被两种方法所确定。
相关链接：
International Stroke Conference
Late-Breaking Science Oral Abstracts：LB11
Publishing Title：Whole Exome Sequencing in Familial Intracranial Aneurysm: Initial
Abstract:
INTRODUCTION: Whole exome sequencing is an innovative approach to identifying rare variants associated with disease but reducing the large number of variants to a useful set of candidate genes is problematic. The relationship between environmental factors (smoking) and rare variants must also be considered.
METHODS: Whole exome sequencing was performed in 32 affected individuals across 7 families with familial intracranial aneurysm (IA). One family included members with either IA or aortic aneurysms. All samples were genotyped (Illumina® OmniExpress) and sequenced (Agilent© SureSelect™ 50Mb Human All Exon Kit). After extensive quality and biologic filters, gene ontology (GO) pathway analysis and linkage analysis were both used to prioritize among the variants identified through whole exome sequencing. Only single nucleotide variants (SNVs) are included in the present analysis. Insertion/deletions are currently being analyzed.
RESULTS: From 103,967 diallelic single nucleotide variants (SNVs) identified, 83% remained after applying quality filters such as frequency of missing loci, excess heterozygosity/homozygosity and strand bias. Variants were further excluded if they were synonymous or non-exonic, or if they had an allele frequency >3%, which left 9% of the original dialleic SNVs. Biological filters kept genes if at least 3 affected individuals in the family shared the same variant (autosomal dominant; heterozygote) or 2 variants in the same gene (autosomal recessive; compound heterozygote or homozygote). Of the 618 SNVs in 537 genes retained, 27 variants in 19 genes were found in selected GO categories and 12 variants in 10 genes were found within 1MB of a tag SNP with a LOD>1.15. Table 1 provides results from one family from the GO analysis. Only one gene LAMA5 (laminin) was identified by both approaches.
CONCLUSIONS: To our knowledge, this is the first preliminary report of whole exome sequencing in FIA families. Using GO and linkage to prioritize SNVs of interest may be powerful approaches to identify variants related to the formation and rupture of aneurysms. Subsequent studies are required to provide more conclusive evidence for the utility of this approach. (Study supported by: R01NS39512 and CIDR NIH Contract Number HHSN268200782096C).
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#全外显子测序#
31
#基因变异#
27
#变异#
25
#外显子测序#
34
#外显子#
36
#家族性#
31