Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.
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基因组变异的综合分析揭示了候选单倍不足基因与先天性心脏病的新关联。
DOI：
10.1371/journal.pgen.1009679
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发表时间：
2021-07
期刊：
影响因子：
4.5
通讯作者：
Hitz MP
中科院分区：
文献类型：
--
作者：
Audain E;Wilsdon A;Breckpot J;Izarzugaza JMG;Fitzgerald TW;Kahlert AK;Sifrim A;Wünnemann F;Perez-Riverol Y;Abdul-Khaliq H;Bak M;Bassett AS;Benson DW;Berger F;Daehnert I;Devriendt K;Dittrich S;Daubeney PE;Garg V;Hackmann K;Hoff K;Hofmann P;Dombrowsky G;Pickardt T;Bauer U;Keavney BD;Klaassen S;Kramer HH;Marshall CR;Milewicz DM;Lemaire S;Coselli JS;Mitchell ME;Tomita-Mitchell A;Prakash SK;Stamm K;Stewart AFR;Silversides CK;Siebert R;Stiller B;Rosenfeld JA;Vater I;Postma AV;Caliebe A;Brook JD;Andelfinger G;Hurles ME;Thienpont B;Larsen LA;Hitz MP
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. Congenital heart disease (CHD) is the most common congenital anomaly and represents a major global health burden. Multiple studies have identified a key genetic component contributing to the aetiology of CHD. However, despite the advances in the field of CHD within the last three decades, the genetic causes underlying CHD are still not fully understood. Herein we have assembled a large patient CHD cohort and performed a data-driven meta-analysis of genomic variants in CHD. This analysis has allowed us to strengthen the disease association of known CHD genes, as well as identifying novel haploinsufficient CHD candidate genes.
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影响因子：
3.7
作者：
Dilg D;Saleh RN;Phelps SE;Rose Y;Dupays L;Murphy C;Mohun T;Anderson RH;Scambler PJ;Chapgier AL
通讯作者：
Chapgier AL
影响因子：
3.5
作者：
Chapman, Gavin;Moreau, Julie L. M.;Dunwoodie, Sally L.
通讯作者：
Dunwoodie, Sally L.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
8
作者：
Andersen, Troels Askhoj;Troelsen, Karin de Linde Lind;Larsen, Lars Allan
通讯作者：
Larsen, Lars Allan
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