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

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Science  04 Dec 2015:
Vol. 350, Issue 6265, pp. 1262-1266
DOI: 10.1126/science.aac9396
  • Fig. 1 Genes with multiple de novo mutations are candidate CHD risk genes.

    (A) Histograms show the expected distribution of the number of genes containing multiple de novo mutations (empirically derived using 1M permutations, black) and the observed number of genes with multiple mutations in cases (red line) for each class. P values were calculated by permutation. (B) Twenty-one genes with multiple damaging de novo mutations in cases. P values are from Poisson test against expectation, with significance threshold <9 × 10−7. Further details are shown in table S6.

  • Fig. 2 Burden of damaging de novo mutations in HHE genes among CHD cases with extracardiac phenotypes.

    (A) The enrichment (ratio of observed to expected) of damaging de novo mutations in HHE genes is shown for each phenotype (±95% confidence interval). Case probands were excluded if they carried de novo mutations in known CHD syndrome genes (n = 19), had unknown extracardiac phenotype for both NDD and CA (n = 6), or had one unknown phenotype and were negative for the other (n = 273). Cases with either CA or NDD and unknown status for the other phenotype (n = 97) were included in the “Extra” category but excluded from the “only” categories. (B) Percent excess of individuals carrying damaging de novo mutations in HHE genes by indicated phenotype (±95% confidence interval). An explanation of the calculation is provided in (12). (C) Table of observed and expected de novo rates for the indicated variant classes by phenotype.

  • Fig. 3 Genes containing de novo mutations in CHD cases show pleiotropic developmental effects.

    (A) Individuals with CHD carry an excess of damaging de novo mutations among 1161 genes identified by containing damaging de novo mutations in seven published studies of NDD (P-NDD cohort) (7, 1823). All CHD cases were subdivided by NDD status (CHD + NDD: n = 417 patients; CHD – NDD: n = 440; unknown NDD: n = 363). P values ≤ 0.005 as indicated (stars) were calculated from a Poisson test against a model-derived distribution (values in table S11). The P-NDD gene set (blue) was further filtered for HHE genes (P-NDD/HHE, red, 564 genes). Enrichments are shown ±95% confidence intervals. (B) Percentile gene expression ranks (100 = high) are shown for all genes (gray) in the developing brain and heart, highlighting 69 genes with damaging de novo mutations in both CHD cases and the P-NDD cohort (blue or purple). Genes with multiple de novo mutations in CHD (red or purple) are shown. The point size represents the numbers of de novo events.

  • Table 1 De novo enrichment in cases versus controls by expectation analysis.

    n, number of de novo mutations; rate, number of de novo mutations divided by the number of individuals in the cohort (N); enrichment, ratio of observed to expected numbers of mutations; HHE, high heart-expressed genes (top quartile of expression); LHE, lower heart-expressed genes (bottom three quartiles of expression); D-Mis, damaging missense predicted by Meta-SVM; Damaging, D-Mis+LoF. Bold numbers indicate enrichment >2 or P < 0.005.

    Cases, N = 1213Controls, N = 900
    ObservedExpectedEnrichmentPObservedExpectedEnrichmentP
    nRatenRatenRatenRate
    All genes
    Total12731.051312.71.081.00.879251.03979.71.090.90.96
    Synonymous2770.23371.40.310.712290.25277.40.310.81
    Missense8460.70824.90.681.00.246140.68615.60.681.00.53
    D-Mis2120.17133.10.111.61.8 × 10−101190.1399.30.111.20.03
    LoF1500.12116.50.101.30.0016820.0986.70.100.90.71
    Damaging3620.30249.50.211.41.5 × 10−112010.22186.00.211.10.14
    HHE genes
    Total4480.37372.40.311.27.8 × 10−052710.30277.70.311.00.66
    Synonymous810.07103.50.090.80.99800.0977.30.091.00.39
    Missense2880.24234.30.191.20.000381630.18174.70.190.90.82
    D-Mis990.0840.60.032.47.7 × 10−15370.0430.30.031.20.13
    LoF790.0734.50.032.36.2 × 10−11280.0325.70.031.10.35
    Damaging1780.1575.10.062.45.1 × 10−24650.0755.90.061.20.13
    LHE genes
    Total8250.68940.30.780.916540.73702.10.780.90.97
    Synonymous1960.16267.80.220.711490.17200.10.220.71
    Missense5580.46590.50.490.90.914510.50440.90.491.00.32
    D-Mis1130.0992.40.081.20.021820.0969.00.081.20.069
    LoF710.0682.00.070.90.9540.0661.10.070.90.83
    Damaging1840.15174.40.141.10.241360.15130.10.141.10.31

Supplementary Materials

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

    Jason Homsy, Samir Zaidi, Yufeng Shen, James S. Ware, Kaitlin E. Samocha, Konrad J. Karczewski, Steven R. DePalma, David McKean, Hiroko Wakimoto, Josh Gorham, Sheng Chih Jin, John Deanfield, Alessandro Giardini, George A. Porter Jr., Richard Kim, Kaya Bilguvar, Francesc López-Giráldez, Irina Tikhonova, Shrikant Mane, Angela Romano-Adesman, Hongjian Qi, Badri Vardarajan, Lijiang Ma, Mark Daly, Amy E. Roberts, Mark W. Russell, Seema Mital, Jane W. Newburger, J. William Gaynor, Roger E. Breitbart, Ivan Iossifov, Michael Ronemus, Stephan J. Sanders, Jonathan R. Kaltman, Jonathan G. Seidman, Martina Brueckner, Bruce D. Gelb, Elizabeth Goldmuntz, Richard P. Lifton, Christine E. Seidman, Wendy K. Chung

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Tables S1 to S12
    • Figs. S1 to S3
    • Captions for Databases S1 to S10
    • References (24–29)
    • Additional Acknowledgments

    Additional Data

    Databases S1 to S10
    Database S1: Phenotypes for each case proband, including cardiac, neurodevelopmental disorders and extra-cardiac congenital anomalies.
    Database S2: List of de novo Mutations in CHD case cohort.
    Database S3: List of de novo Mutations in Control cohort.
    Database S4: List of de novo probabilities for each variant class in each protein-coding gene on the Nimblegen V2 exome, adjusted for depth in Cases.
    Database S5: List of de novo probabilities for each variant class in each protein-coding gene on the Nimblegen V2 exome, adjusted for depth in Controls.
    Database S6: Functional term enrichment analysis of all Genes with Damaging (loss of function + deleterious missense) de novo mutations in all cases.
    Database S7: Functional term enrichment analysis of all Genes with Loss of Function de novo mutations in 860 new cases.
    Database S8: List of 1,563 variants (1,161 unique genes) with damaging de novo mutations from 7 independent NDD cohorts.
    Database S9: Functional term enrichment analysis among 69 genes with Damaging de novo mutations overlapping between CHD cases and the published NDD (P-NDD) cohort.
    Database S10: Percentile ranks of genes by expression in the developing mouse heart and brain.

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