We have found that copy-number variations underlie ~10-15% of human heterotaxy. The initial analysis of 362 patients with severe CHD demonstrated that de-novo mutations underlie ~10% of CHD. Expansion of the patient cohort to over 1,100 patients showed a link between the genetic cause of CHD and neurodevelopmental outcome.

Analysis of mutations identified from CHD patients has already led us to new insights into the mechanism of early heart development, including how the glycosylation enzyme GALNT11 modulates NOTCH signaling in determining cilia identity in the development of LR asymmetry, and how the NIMA-like kinase Nek2 balances ciliogenesis and resorption.

Finally, increasing the size of the studied CHD cohort coupled with a novel computational approach for the first time allowed the unbiased identification of inherited variants contributing to human disease, and identified that mutations affecting cilia genes contribute directly to human CHD.

Current work is focused on expanding the understanding of the genetic underpinnings of congenital heart disease through large-scale genomic analyses of patients with CHD, including exploration of inherited contributions to CHD, and potential multigenic inheritance. We are also developing methods to link large genomic datasets such as those generated by the PCGC to clinical datasets including the electronic medical record and the STS (Society of Thoracic Surgeons) databases.

Selected Publications:

K.A. Fakhro, M. Choi, S.M. Ware, J.W. Belmont, J.A. Towbin, R.P. Lifton, M.K. Khokha, M. Brueckner. Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. PMID: 21282601 PNAS, 108(7):2915-20 (2011)

S. Zaidi, M. Choi, H. Wakimoto, L. Ma, J. Jiang, J.D. Overton, A. Romano- Adesman, R.D. Bjornson, R.E. Breitbart, K.K. Brown, N.J. Carriero, Y.H. Cheung, J. Deanfield, S. Depalma, K.A. Fakhro , J. Glessner, H. Hakonarson, M.J. Italia, J. Kaltman, J. Kaski, R. Kim, J.K. Kline, T. Lee, J. Leipzig, A. Lopez, S.M. Mane, L.E. Mitchell, J.W. Newburger, M. Parfeno, I. Pe'er, G. Porter, A.E. Roberts, R. Sachidanandam, S.J. Sanders, H.S. Seiden, M.W. State, S. Subramanian, I.R. Tikhonova, W. Wang, D. Warburton, P.S. White, I.A. Williams, H. Zhao, J.G. Seidman, M. Brueckner (co-corresponding author), W.K. Chung, B.D. Gelb, E. Goldmuntz, C.E. Seidman, R.P. Lifton. De novo mutations in histone-modifying genes in congenital heart disease. PMID: 23665959 Nature, 498:220-223 (2013)

J. Homsy, S. Zaidi, Y. Shen, J.S. Ware, K.E. Samocha, K.J. Karczewski, S.R. DePalma, D. McKean, H. Wakimoto, J. Gorham, S.C. Jin, J. Deanfield, A. Giardini, G.A. Porter Jr, R. Kim, K. Bilguvar, F. López-Giráldez, I. Tikhonova, S. Mane, A. Romano-Adesman, H. Qi, B. Vardarajan, L. Ma, M. Daly, A.E. Roberts, M.W. Russell, S. Mital, J.W. Newburger, J.W. Gaynor, R.E. Breitbart, I. Iossifov, M. Ronemus, S.J. Sanders, J.R. Kaltman, J.G. Seidman, M. Brueckner (co-corresponding author), B.D. Gelb, E. Goldmuntz, R.P. Lifton, C.E. Seidman, W.K. Chung. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. PMID: 26785492 Science 350(6265):1262-6 (2015)

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. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. PMID: 28991257 Nature Genetics 49(11):1593-1601 (2017)

Watkins WS, Hernandez EJ, Wesolowski S, Bisgrove BW, Sunderland RT, Lin E, Lemmon G, Demarest BL, Miller TA, Bernstein D, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Newburger JW, Seidman CE, Shen Y, Yost HJ, Yandell M, Tristani-Firouzi M. De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes. Nat Commun. 2019 Oct 17; 2019 Oct 17. PMID: 31624253.