Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.
Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.
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DOI：
10.1186/2040-2392-5-1
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发表时间：
2014-01-10
期刊：
影响因子：
6.2
通讯作者：
Pericak-Vance MA
中科院分区：
文献类型：
--
作者：
Cukier HN;Dueker ND;Slifer SH;Lee JM;Whitehead PL;Lalanne E;Leyva N;Konidari I;Gentry RC;Hulme WF;Booven DV;Mayo V;Hofmann NK;Schmidt MA;Martin ER;Haines JL;Cuccaro ML;Gilbert JR;Pericak-Vance MA
自闭症谱系障碍（ASDs）包含一系列严重程度各异的神经发育状况，其特征是在社会关联性、沟通和行为方面存在显著的质的困难。尽管有大量证据表明其具有高度遗传性，但迄今为止的遗传学研究结果显示，自闭症的病因极其复杂多样，且仅有一小部分自闭症相关基因被发现。
为了帮助解开这种遗传复杂性，我们对来自40个有多个远亲患病个体的家庭的100名自闭症患者进行了全外显子组测序。所有家庭至少包含一对患自闭症的表亲。每个个体都使用安捷伦SureSelect人类全外显子组试剂盒进行捕获，在Illumina Hiseq 2000上进行测序，所得数据使用Burrows - Wheeler比对器（BWA）、基因组分析工具包（GATK）和SeattleSeq进行处理和注释。利用每个家庭的基因分型信息来确定通过遗传同一（IBD）的基因组区域。然后对通过外显子组测序确定的、出现在IBD区域且存在于每个家庭所有患病个体中的变异进行评估，以确定哪些可能与疾病相关。优先考虑那些新颖且罕见（次要等位基因频率，MAF小于0.05）且预计会有害的核苷酸改变，无论是通过改变氨基酸还是剪接模式。
我们在先前与自闭症无关的基因中发现了许多潜在的有害的、与自闭症相关的风险变异。这些基因的一部分与其他神经行为障碍有关，包括抑郁症（SLIT3）、癫痫（CLCN2、PRICKLE1）、智力障碍（AP4M1）、精神分裂症（WDR60）和图雷特综合征（OFCC1）。在先前报道的自闭症候选基因中也发现了其他改变，包括在多个家庭中存在改变的三个基因（CEP290、CSMD1、FAT1和STXBP5）。我们从文献中整理了一份自闭症候选基因列表，确定自闭症候选基因中的变异发生频率比外显子组测序所捕获的随机基因高1.65倍（P = 8.55×10⁻⁵）。
通过研究这些独特的家系，我们发现了与自闭症相关的新型DNA变异，证明了在大家庭中进行外显子组测序是发现自闭症候选基因的有力工具，并为广泛的神经发育和神经精神疾病的潜在遗传成分提供了进一步的证据。
Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10-5). By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
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影响因子：
5.3
作者：
Gauthier J;Siddiqui TJ;Huashan P;Yokomaku D;Hamdan FF;Champagne N;Lapointe M;Spiegelman D;Noreau A;Lafrenière RG;Fathalli F;Joober R;Krebs MO;DeLisi LE;Mottron L;Fombonne E;Michaud JL;Drapeau P;Carbonetto S;Craig AM;Rouleau GA
通讯作者：
Rouleau GA
影响因子：
5.3
作者：
Casey JP;Magalhaes T;Conroy JM;Regan R;Shah N;Anney R;Shields DC;Abrahams BS;Almeida J;Bacchelli E;Bailey AJ;Baird G;Battaglia A;Berney T;Bolshakova N;Bolton PF;Bourgeron T;Brennan S;Cali P;Correia C;Corsello C;Coutanche M;Dawson G;de Jonge M;Delorme R;Duketis E;Duque F;Estes A;Farrar P;Fernandez BA;Folstein SE;Foley S;Fombonne E;Freitag CM;Gilbert J;Gillberg C;Glessner JT;Green J;Guter SJ;Hakonarson H;Holt R;Hughes G;Hus V;Igliozzi R;Kim C;Klauck SM;Kolevzon A;Lamb JA;Leboyer M;Le Couteur A;Leventhal BL;Lord C;Lund SC;Maestrini E;Mantoulan C;Marshall CR;McConachie H;McDougle CJ;McGrath J;McMahon WM;Merikangas A;Miller J;Minopoli F;Mirza GK;Munson J;Nelson SF;Nygren G;Oliveira G;Pagnamenta AT;Papanikolaou K;Parr JR;Parrini B;Pickles A;Pinto D;Piven J;Posey DJ;Poustka A;Poustka F;Ragoussis J;Roge B;Rutter ML;Sequeira AF;Soorya L;Sousa I;Sykes N;Stoppioni V;Tancredi R;Tauber M;Thompson AP;Thomson S;Tsiantis J;Van Engeland H;Vincent JB;Volkmar F;Vorstman JA;Wallace S;Wang K;Wassink TH;White K;Wing K;Wittemeyer K;Yaspan BL;Zwaigenbaum L;Betancur C;Buxbaum JD;Cantor RM;Cook EH;Coon H;Cuccaro ML;Geschwind DH;Haines JL;Hallmayer J;Monaco AP;Nurnberger JI Jr;Pericak-Vance MA;Schellenberg GD;Scherer SW;Sutcliffe JS;Szatmari P;Vieland VJ;Wijsman EM;Green A;Gill M;Gallagher L;Vicente A;Ennis S
通讯作者：
Ennis S
影响因子：
12.3
作者：
Carroll LS;Owen MJ
通讯作者：
Owen MJ
DOI：
10.1126/science.1212673
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fryer JD;Yu P;Kang H;Mandel-Brehm C;Carter AN;Crespo-Barreto J;Gao Y;Flora A;Shaw C;Orr HT;Zoghbi HY
通讯作者：
Zoghbi HY
影响因子：
5.2
作者：
Glancy, Mary;Barnicoat, Angela;Barber, John C. K.
通讯作者：
Barber, John C. K.