The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

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Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

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Figure 1: Characterization of BCAs detected by karyotyping at nucleotide resolution.
Figure 2: De novo BCAs associated with congenital anomalies disrupt functionally relevant loci.
Figure 3: Recurrent disruption of long-range regulatory interactions at the 5q14.3 locus.
Figure 4: Correlations between phenotypes and genes disrupted in subjects harboring pathogenic BCAs.


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We are deeply grateful for the seminal work led by our co-author, Dorothy Warburton, who passed away during review of this manuscript. Dr. Warburton was a pioneer in cytogenetic research and a close colleague, mentor, and friend to so many in the cytogenetics community.

We wish to thank all subjects and families who have been enrolled in this study, as well as the countless genetic counselors and clinical geneticists who contributed to the ascertainment of subjects. This study was supported by the National Institutes of Health (grant GM061354 to M.E.T., J.F.G., C.C.M., and E.L.; grants MH095867 and HD081256 to M.E.T.), the March of Dimes (6-FY15-255 to M.E.T.), the European Molecular Biology Organization and the Marie Curie Actions of the European Commission (fellowship EMBO ALTF-183-2015 to C.R.), the Bettencourt-Schueller Foundation (young investigator award to C.R.), the Philippe Foundation (award to C.R.), the Harvard Medical School–Portugal Program in Translational and Clinical Research and Health Information (Fundação para a Ciência e a Tecnologia, HMSP-ICT/0016/2013 to C.C.M. and D.D.), the National Science Foundation (NSF Graduate Research Fellowship DGE1144152 to S.L.P.S.), the Fund for Scientific Research–Flanders (B.C. and S.V. are an FWO senior clinical investigator and an FWO postdoctoral researcher, respectively), Clinical Medicine Science and Technology Projects of Jiangsu Province (grant BL2013019 to Haibo Li and Hong Li), the Suzhou Key Medical Center (grant Szzx201505 to Haibo Li and Hong Li), and the Royal Society of New Zealand (Rutherford Discovery Fellowship to J.C.J.). This study was also supported by the Desmond and Ann Heathwood MGH Research Scholars award to M.E.T.

Author information

M.E.T., J.F.G., C.C.M., E.C.T., J.C.H., W.P.K., N.d.L., and H.G.B. designed the study. C.R., H.B., R.L.C., V.P., I.B., C.C., J.T.G., M.R.S., M.J.v.R., and W.P.K. performed computational analyses. C.H., C.M.S., R.A., M.-A. Anderson, C.A., E.C., B.B.C., J.K., W.L., P.M., L.M., T. Mason, D.P., J.R., M.J.W., and A.W. performed cellular, molecular, or genomic experiments. T.K., E. Mitchell, J.C.H., M.-A. Abbott, O.A.A.-R., E.A., S.L.A.-E., F.S.A., Y.A., K.A.-Y., J.F.A., T.B., J.A.B., E.B., E.M.H.F.B., E.H.B., C.W.B., H.T.B., B.C., K.C., H.C., T.C., D.D., M.A.D., A.D., M.D'H., B.B.A.d.V., D.L.E., H.L.F., H.F., D.R.F., P.G., D.G., T.G., M.G., B.H.G., C.G., K.W.G., A.L.G., A.H.-K., D.J.H., M.A.H., R. Hill, R. Hochstenbach, J.D.H., R.J.H., M.W.H., A.M.I., M. Irons, M. Irving, J.C.J., S.J., T.J., J.P.J., M.C.J., S.G.K., D.A.K., P.M.K., Y.L., E.L., K.L., A.V.L., Haibo Li, Hong Li, E.C.L., C.L., E.J.L., D.L., M.J.M., G. Mandrile, C.L.M., D.M.-F., M.W.M., C.J.Z.M., B.M., S. Middelkamp, L.R.M., E. Moe, S. Mohammed, T. Mononen, M.E.M., G. Moya, A.W.N., Z.O., S. Parkash, S.P.P., S. Pereira, K.P., R.E.P.A., P.J.P., G.P., S.R., L.R., W.R., D.R., I.R., F.R., P.R., S.L.P.S., R. Shaheen, R. Sparkes, E.S., B.S., J.T., J.V.T., B.W.v.B., J.v.d.K., I.v.D.B., T.v.E., C.M.v.R.-A., S.V., C.M.L.V.-T., D.P.W., S.W., M.d.l.C.A.Y.-d.V., R.T.Z., B.L., H.G.B., N.d.L., W.P.K., E.C.T., C.C.M., and J.F.G. ascertained and enrolled subjects and provided phenotypic information. C.R. and M.E.T. wrote the manuscript, which was approved by all authors.

Correspondence to Michael E Talkowski.

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