Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences.
Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences.
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DOI：
10.3389/fgene.2020.00957
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发表时间：
2020
影响因子：
3.7
通讯作者：
Bassett AS
中科院分区：
文献类型：
--
作者：
Manshaei R;Merico D;Reuter MS;Engchuan W;Mojarad BA;Chaturvedi R;Heung T;Pellecchia G;Zarrei M;Nalpathamkalam T;Khan R;Okello JBA;Liston E;Curtis M;Yuen RKC;Marshall CR;Jobling RK;Oechslin E;Wald RM;Silversides CK;Scherer SW;Kim RH;Bassett AS
最近对罕见遗传变异的全基因组研究已经开始涉及法洛四联症（TOF），一种严重的先天性心脏病（CHD）的新机制。为了给没有父母基因组的病例数据提供统计学支持，我们重新分析了231名TOF（n = 175）或相关CHD患者的基因组序列。我们采用了最初为从头变异开发的负荷测试，以评估单个基因以及与功能途径和小鼠表型相对应的基因组中的超罕见变异负荷，解释了高度相关的基因组和多重测试。对于截短变体，基因负荷检验证实了FLT 4中的显著负荷（Bonferroni校正的p值< 0.01）。对于错义变体，NOTCH 1中的负荷仅在限制于受约束基因时实现全基因组显著性（即，在阴性选择下，Bonferroni校正p值= 0.004），并且显示影响胞外结构域的变体的富集，特别是破坏形成二硫键的半胱氨酸残基的那些（OR = 39.8相对于gnomAD）。NOTCH 1超罕见错义变异的个体，都有TOF，富含CHD阳性家族史。其他先前未涉及CHD的基因在基因负荷试验中得到了更适度的统计学支持。用于截短变体的基因组负荷测试鉴定了对应于VEGF信号传导（FDR = 0%）的途径簇和对应于异常脉管系统（FDR = 0.8%）的小鼠表型簇;这些表明了先前未鉴定的另外的候选基因（例如，WNT 5A和ZFAND 5）。最有希望的基因的结果由群组的TOF子集驱动。这些发现支持了超罕见变异破坏TOF遗传结构中参与VEGF和NOTCH信号传导的基因的重要性，占TOF队列中个体的11-14%。这些原理证明数据表明，这种统计方法可以帮助分析仅病例测序数据，其中超罕见变异，无论是新生的还是遗传的，都有助于复杂疾病的遗传病因。
Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF (n = 175) or related CHD. We adapted a burden test originally developed for de novo variants to assess ultra-rare variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets and for multiple testing. For truncating variants, the gene burden test confirmed significant burden in FLT4 (Bonferroni corrected p-value < 0.01). For missense variants, burden in NOTCH1 achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni corrected p-value = 0.004), and showed enrichment for variants affecting the extracellular domain, especially those disrupting cysteine residues forming disulfide bonds (OR = 39.8 vs. gnomAD). Individuals with NOTCH1 ultra-rare missense variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in CHD had more modest statistical support in gene burden tests. Gene-set burden tests for truncating variants identified a cluster of pathways corresponding to VEGF signaling (FDR = 0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR = 0.8%); these suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Results for the most promising genes were driven by the TOF subset of the cohort. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF, accounting for 11–14% of individuals in the TOF cohort. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.
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影响因子：
3.3
作者：
Fearnley GW;Odell AF;Latham AM;Mughal NA;Bruns AF;Burgoyne NJ;Homer-Vanniasinkam S;Zachary IC;Hollstein MC;Wheatcroft SB;Ponnambalam S
通讯作者：
Ponnambalam S
影响因子：
16.2
作者：
Parmantier, E;Lynn, B;Mirsky, R
通讯作者：
Mirsky, R
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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影响因子：
30.8
作者：
Jin SC;Homsy J;Zaidi S;Lu Q;Morton S;DePalma SR;Zeng X;Qi H;Chang W;Sierant MC;Hung WC;Haider S;Zhang J;Knight J;Bjornson RD;Castaldi C;Tikhonoa IR;Bilguvar K;Mane SM;Sanders SJ;Mital S;Russell MW;Gaynor JW;Deanfield J;Giardini A;Porter GA Jr;Srivastava D;Lo CW;Shen Y;Watkins WS;Yandell M;Yost HJ;Tristani-Firouzi M;Newburger JW;Roberts AE;Kim R;Zhao H;Kaltman JR;Goldmuntz E;Chung WK;Seidman JG;Gelb BD;Seidman CE;Lifton RP;Brueckner M
通讯作者：
Brueckner M
影响因子：
14.9
作者：
Bult CJ;Blake JA;Smith CL;Kadin JA;Richardson JE;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group