干旱区生态环境知识资源中心(Arid): Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences

Arid

DOI	10.3389/fgene.2020.00957
	Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences
	Manshaei, Roozbeh; Merico, Daniele; Reuter, Miriam S.; Engchuan, Worrawat; Mojarad, Bahareh A.; Chaturvedi, Rajiv; Heung, Tracy; Pellecchia, Giovanna; Zarrei, Mehdi; Nalpathamkalam, Thomas; Khan, Reem; Okello, John B. A.; Liston, Eriskay; Curtis, Meredith; Yuen, Ryan K. C.; Marshall, Christian R.; Jobling, Rebekah K.; Oechslin, Erwin; Wald, Rachel M.; Silversides, Candice K.; Scherer, Stephen W.; Kim, Raymond H.; Bassett, Anne S.
通讯作者	Bassett, AS
来源期刊	FRONTIERS IN GENETICS
EISSN	1664-8021
出版年	2020
卷号	11
英文摘要	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 forde novovariants 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 inFLT4(Bonferroni correctedp-value < 0.01). For missense variants, burden inNOTCH1achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni correctedp-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 withNOTCH1ultra-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.,WNT5AandZFAND5). 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, whetherde novoor inherited, contribute to the genetic etiopathogenesis of a complex disorder.
英文关键词	tetralogy of fallot heart disease whole genome sequencing NOTCH1 FLT4 rare variants
类型	Article
语种	英语
开放获取类型	Green Submitted, Green Published, gold
收录类别	SCI-E
WOS记录号	WOS:000576139600001
WOS关键词	CONGENITAL HEART-DISEASE ; DESERT-HEDGEHOG ; WNT5A MUTATIONS ; MISSENSE ; ANGIOGENESIS ; CONTRIBUTE ; ISOFORMS ; KLOTHO ; GROWTH
WOS类目	Genetics & Heredity
WOS研究方向	Genetics & Heredity
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/326670
作者单位	[Manshaei, Roozbeh; Reuter, Miriam S.; Chaturvedi, Rajiv; Khan, Reem; Okello, John B. A.; Liston, Eriskay; Curtis, Meredith; Jobling, Rebekah K.; Kim, Raymond H.] Hosp Sick Children, Ted Rogers Ctr Heart Res, Cardiac Genome Clin, Toronto, ON, Canada; [Merico, Daniele] Deep Genom Inc, Toronto, ON, Canada; [Merico, Daniele; Reuter, Miriam S.; Engchuan, Worrawat; Pellecchia, Giovanna; Zarrei, Mehdi; Nalpathamkalam, Thomas; Yuen, Ryan K. C.; Marshall, Christian R.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada; [Mojarad, Bahareh A.; Zarrei, Mehdi; Yuen, Ryan K. C.; Scherer, Stephen W.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada; [Chaturvedi, Rajiv; Wald, Rachel M.] Hosp Sick Children, Div Cardiol, Labatt Heart Ctr, Toronto, ON, Canada; [Heung, Tracy; Bassett, Anne S.] Ctr Addict & Mental Hlth, Clin Genet Res Program, Toronto, ON, Canada; [Heung, Tracy; Bassett, Anne S.] Univ Hlth Network, Dalglish Family 22q Clin, Toronto, ON, Canada; [Yuen, Ryan K. C.;...
推荐引用方式 GB/T 7714	Manshaei, Roozbeh,Merico, Daniele,Reuter, Miriam S.,et al. Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences[J],2020,11.
APA	Manshaei, Roozbeh.,Merico, Daniele.,Reuter, Miriam S..,Engchuan, Worrawat.,Mojarad, Bahareh A..,...&Bassett, Anne S..(2020).Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences.FRONTIERS IN GENETICS,11.
MLA	Manshaei, Roozbeh,et al."Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences".FRONTIERS IN GENETICS 11(2020).