De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Homsy, J., Zaidi, S., Shen, Y., Ware, J. S., Samocha, K. E., Karczewski, K. J., DePalma, S. R., McKean, D., Wakimoto, H., Gorham, J., Jin, S. C., Deanfield, J., Giardini, A., Porter G.A, Jr., Kim, R., Bilguvar, K., López-Giráldez, F., Tikhonova, I., Mane, S., Romano-Adesman, A., Qi, H., Vardarajan, B., Ma, L., Daly, M., Roberts, A. E., Russell, M. W., Mital, S., Newburger, J. W., Gaynor, J. W., Breitbart, R. E., Iossifov, I., Ronemus, M., Sanders, S. J., Kaltman, J. R., Seidman, J. G., Brueckner, M., Gelb, B. D., Goldmuntz, E., Lifton, R. P., Seidman, C. E., Chung, W. K. (December 2015) De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science, 350 (6265). pp. 1262-1266. ISSN 00368075

URL: http://www.ncbi.nlm.nih.gov/pubmed/26785492
DOI: 10.1126/science.aac9396

Abstract

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2%of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator ofmRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Item Type: Paper
Subjects: diseases & disorders > cardiovascular diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > de novo mutation
neurobiology
CSHL Authors:
Communities: CSHL labs > Iossifov lab
CSHL labs > Wigler lab
Depositing User: Matt Covey
Date: 4 December 2015
Date Deposited: 14 Dec 2015 20:41
Last Modified: 11 Jan 2017 16:04
PMCID: PMC4890146
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32173

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