Sequencing of a Chinese Tetralogy of Fallot Cohort Reveals Clustering Mutations in Myogenic Heart Progenitors

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2021 Dec 14

PMID 34905512

Citations 4

Authors

Clara Sze Man Tang

Mimmi Mononen

Wai-Yee Lam

Sheng Chih Jin

Xuehan Zhuang

Maria-Merce Garcia-Barcelo

Qiongfen Lin

Yujia Yang

Makoto Sahara

Elif Eroglu

Kenneth R Chien

Haifa Hong

Paul Kwong Hang Tam

Peter J Gruber

Affiliations

Soon will be listed here.

Abstract

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

Citing Articles

A splicing variant in EFCAB7 hinders ciliary transport and disrupts cardiac development.

Yang X, Wang Q, Li T, Zhou Y, Gao J, Ma W J Biol Chem. 2025; 301(3):108249.

PMID: 39894222 PMC: 11889548. DOI: 10.1016/j.jbc.2025.108249.

A novel homozygous splice donor variant in the gene causing Leigh syndrome with epilepsy, a French-Canadian disorder in a Saudi family: case report.

Muthaffar O, Abdulkareem A, Ashi A, Naseer M Front Pediatr. 2023; 11:1288542.

PMID: 38046674 PMC: 10690952. DOI: 10.3389/fped.2023.1288542.

Artificial intelligence-based approaches for the detection and prioritization of genomic mutations in congenital surgical diseases.

Lin Q, Tam P, Tang C Front Pediatr. 2023; 11:1203289.

PMID: 37593442 PMC: 10429173. DOI: 10.3389/fped.2023.1203289.

Evaluating High-Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses.

Chui M, Mak C, Yu M, Wong S, Lun K, Yung T J Am Heart Assoc. 2023; 12(4):e028226.

PMID: 36789878 PMC: 10111484. DOI: 10.1161/JAHA.122.028226.

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of .

Wang J, Wang C, Xie H, Feng X, Wei L, Wang B Front Cardiovasc Med. 2022; 9:863650.

PMID: 35872890 PMC: 9300848. DOI: 10.3389/fcvm.2022.863650.

References

Asp M, Giacomello S, Larsson L, Wu C, Furth D, Qian X . A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart. Cell. 2019; 179(7):1647-1660.e19. DOI: 10.1016/j.cell.2019.11.025. View

Laurie C, Laurie C, Rice K, Doheny K, Zelnick L, McHugh C . Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012; 44(6):642-50. PMC: 3366033. DOI: 10.1038/ng.2271. View

Sylva M, van den Hoff M, Moorman A . Development of the human heart. Am J Med Genet A. 2013; 164A(6):1347-71. DOI: 10.1002/ajmg.a.35896. View

Mummery C, Zhang J, Ng E, Elliott D, Elefanty A, Kamp T . Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ Res. 2012; 111(3):344-58. PMC: 3578601. DOI: 10.1161/CIRCRESAHA.110.227512. View

Apitz C, Webb G, Redington A . Tetralogy of Fallot. Lancet. 2009; 374(9699):1462-71. DOI: 10.1016/S0140-6736(09)60657-7. View

Hehir-Kwa J, Pfundt R, Veltman J . Exome sequencing and whole genome sequencing for the detection of copy number variation. Expert Rev Mol Diagn. 2015; 15(8):1023-32. DOI: 10.1586/14737159.2015.1053467. View

Page D, Miossec M, Williams S, Monaghan R, Fotiou E, Cordell H . Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. Circ Res. 2018; 124(4):553-563. PMC: 6377791. DOI: 10.1161/CIRCRESAHA.118.313250. View

Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S . Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003; 362(9393):1366-73. DOI: 10.1016/s0140-6736(03)14632-6. View

Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O . Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999; 116(5):1141-8. DOI: 10.1016/s0016-5085(99)70017-x. View

10.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

11.

Baban A, Postma A, Marini M, Trocchio G, Santilli A, Pelegrini M . Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot. Am J Med Genet A. 2014; 164A(12):3100-7. DOI: 10.1002/ajmg.a.36783. View

12.

Alankarage D, Ip E, Szot J, Munro J, Blue G, Harrison K . Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genet Med. 2018; 21(5):1111-1120. DOI: 10.1038/s41436-018-0296-x. View

13.

Goldmuntz E, Geiger E, Benson D . NKX2.5 mutations in patients with tetralogy of fallot. Circulation. 2001; 104(21):2565-8. DOI: 10.1161/hc4601.098427. View

14.

Lin Y, Guo X, Zhao B, Liu J, Da M, Wen Y . Association analysis identifies new risk loci for congenital heart disease in Chinese populations. Nat Commun. 2015; 6:8082. DOI: 10.1038/ncomms9082. View

15.

Marelli A, Ionescu-Ittu R, Mackie A, Guo L, Dendukuri N, Kaouache M . Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation. 2014; 130(9):749-56. DOI: 10.1161/CIRCULATIONAHA.113.008396. View

16.

Yang Y, Li H, Cao X, Wang Q, Qiao C, Ya J . Second heart field and the development of the outflow tract in human embryonic heart. Dev Growth Differ. 2013; 55(3):359-67. DOI: 10.1111/dgd.12050. View

17.

Ware J, Samocha K, Homsy J, Daly M . Interpreting de novo Variation in Human Disease Using denovolyzeR. Curr Protoc Hum Genet. 2015; 87:7.25.1-7.25.15. PMC: 4606471. DOI: 10.1002/0471142905.hg0725s87. View

18.

Yang Y, Gharibeh L, Li R, Xin Y, Wang J, Liu Z . GATA4 loss-of-function mutations underlie familial tetralogy of fallot. Hum Mutat. 2013; 34(12):1662-71. DOI: 10.1002/humu.22434. View

19.

Karczewski K, Francioli L, Tiao G, Cummings B, Alfoldi J, Wang Q . The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020; 581(7809):434-443. PMC: 7334197. DOI: 10.1038/s41586-020-2308-7. View

20.

Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z . GATA4 mutations in 486 Chinese patients with congenital heart disease. Eur J Med Genet. 2008; 51(6):527-35. DOI: 10.1016/j.ejmg.2008.06.005. View