Genetic Basis of Human Congenital Heart Disease
Congenital heart disease is one of the most common birth defects, affecting up to 1% of live births. Despite its prevalence, the causes of congenital heart disease are not well understood. A genetic contribution is strongly suggested by the finding that congenital heart disease often occurs in conjunction with chromosome anomalies. To elucidate the genetic basis for human congenital heart disease, we are undertaking a large scale mouse mutagenesis screen to recover mutations in mice causing congenital heart disease. In parallel to these mouse studies, we have an ongoing IRB approved human clinical study protocol to investigate the genetic causes of human congenital heart disease. In addition to facilitate our understanding of the evolutionary conservation of genetic pathways in heart development we are using zebrafish to model the early events of cardiogenesis and human congenital heart disease. These studies entail the use of state of the art high throughput next generation sequencing technology to identify genes that may contribute to human congenital heart disease. As part of this study, we are also investigating whether defects involving the cilia, motile or nonmotile hair-like protrusions on the cell surface, may play an important role in human congenital heart disease and in respiratory complications associated with these patients. The long-term goal of these studies is to elucidate the genetic causes of human congenital heart disease to optimize patient care and help improve the prognosis of children and surviving adults with congenital heart disease. This may include the development of new comprehensive genetic tests for the diagnosis of congenital heart disease and changes in the standard of care to include screening for ciliary dysfunction and better clinical management of patients at risk for respiratory complications due to ciliary dysfunction.
Mouse Hypoplastic left heart Syndrome Mutants. Necropsy (top) and ECM (bottom) histopathology images of the same mutant heart from six of the eight mutant mouse lines identified with hypoplastic left heart syndrome (HLHS) from the Lo lab mouse mutagenesis screen. Ao, aorta; PA, pulmonary artery; LV, left ventricle; RV, right ventricle; MV, mitral valve; LA, left atrium; RA, right atrium.
Exome-chip meta-analysis indetifies novel loci associated with cardiac conduction, including ADAMTS6
Prins BP, Mead TJ, Brody JA, Sveinbjornsson G, Ntalla I, Bihlmeyer NA, van den Berg M, Bork-Jensen J, Cappellani S, Van Duijvenboden S, Klena NT, Gabriel GC, Liu X, Gulec C, Grarup N, Haessler J, Hall LM, Iorio A, Isaacs A, Li-Gao R, Lin H, Liu CT, Lyytikäinen LP, Marten J, Mei H, Müller-Nurasyid M, Orini M, Padmanabhan S, Radmanesh F, Ramirez J, Robino A, Schwartz M, van Setten J, Smith AV, Verweij N, Warren HR, Weiss S, Alonso A, Arnar DO, Bots ML, de Boer RA, Dominiczak AF, Eijgelsheim M, Ellinor PT, Guo X, Felix SB, Harris TB, Hayward C, Heckbert SR, Huang PL, Jukema JW, Kähönen M, Kors JA, Lambiase PD, Launer LJ, Li M, Linneberg A, Nelson CP, Pedersen O, Perez M, Peters A, Polasek O, Psaty BM, Raitakari OT, Rice KM, Rotter JI, Sinner MF, Soliman EZ, Spector TD, Strauch K, Thorsteinsdottir U, Tinker A, Trompet S, Uitterlinden A, Vaartjes I, van der Meer P, Völker U, Völzke H, Waldenberger M, Wilson JG, Xie Z, Asselbergs FW, Dörr M, van Duijn CM, Gasparini P, Gudbjartsson DF, Gudnason V, Hansen T, Kääb S, Kanters JK, Kooperberg C, Lehtimäki T, Lin HJ, Lubitz SA, Mook-Kanamori DO, Conti FJ, Newton-Cheh CH, Rosand J, Rudan I, Samani NJ, Sinagra G, Smith BH, Holm H, Stricker BH, Ulivi S, Sotoodehnia N, Apte SS, van der Harst P, Stefansson K, Munroe PB, Arking DE, Lo CW, Jamshidi Y.
Genome Biol. 2018 Jul 17;19(1):87.
The complex genetics of hypoplastic left heart syndrome.
Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC, Chen Z, Peterson KA, Li Y, Schwartz MC, Reynolds WT, Saydmohammed M, Gibbs B, Wu Y, Devine W, Chatterjee B, Klena NT, Kostka D, de Mesy Bentley KL, Ganapathiraju MK, Dexheimer P, Leatherbury L, Khalifa O, Bhagat A, Zahid M, Pu W, Watkins S, Grossfeld P, Murray SA, Porter GA Jr, Tsang M, Martin LJ, Benson DW, Aronow BJ, Lo CW.
Nat Genet. 2017 Jul;49(7):1152-1159.
DNAH6 and its Interactions with PCD genes in heterotaxy and Primary Ciliary Dyskinesia.
Li Y, Yagi H, Onuoha EO, Damerla RR, Francis R, Furutani Y, Tariq M, King SM, Hendricks G, Cui C, Saydmohammed M, Lee DM, Zahid M, Sami I, Leatherbury L, Pazour GJ, Ware SM, Nakanishi T, Goldmuntz E, Tsang M, Lo CW.
PLoS Genet. 2016 Feb 26;12(2):e1005821.
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.
Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study.
Nat Genet. 2015 Nov;47(11):1363-9.
MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates.
Guimier A, Gabriel GC, Bajolle F, Tsang M, Liu H, Noll A, Schwartz M, El Malti R, Smith LD, Klena NT, Jimenez G, Miller NA, Oufadem M, Moreau de Bellaing A, Yagi H, Saunders CJ, Baker CN, Di Filippo S, Peterson KA, Thiffault I, Bole-Feysot C, Cooley LD, Farrow EG, Masson C, Schoen P, Deleuze JF, Nitschké P, Lyonnet S, de Pontual L, Murray SA, Bonnet D, Kingsmore SF, Amiel J, Bouvagnet P, Lo CW, Gordon CT.
Nat Genet. 2015 Nov;47(11):1260-3.
Global genetic analysis in mice unveils central role for cilia in congenital heart disease
Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW.
Nature. 2015 May 28;521(7553):520-4.