Quantifying the contribution of recessive coding variation to developmental disorders

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Science  07 Dec 2018:
Vol. 362, Issue 6419, pp. 1161-1164
DOI: 10.1126/science.aar6731
  • Fig. 1 Clinical features of DDD probands analyzed here.

    Proportion of probands in different groups with clinical features indicated, extracted from Human Phenotype Ontology terms. Asterisks indicate nominally significant differences between indicated groups (Fisher’s exact test).

  • Fig. 2 Contribution of recessive coding variants to genetic architecture in this study.

    (A) Number of observed and expected biallelic genotypes per individual across all genes. Nominally significant P values from a Poisson test of enrichment are shown. (B) (Left) Number of probands grouped by diagnostic category. The inherited dominant and X-linked diagnoses (narrow pink bar) include only those in known genes, whereas the proportion of probands with de novo and recessive coding diagnoses was inferred as described in (10), including those in as-yet-undiscovered genes. (Right) The proportion of probands in various patient subsets inferred to have diagnostic variants in the indicated classes.

  • Fig. 3 Functional consequences of the pathogenic EIF3F recessive missense variant.

    (A) The Phe232→Val variant impairs translation. Plot shows median fluorescence intensity (MFI) in iPSC lines heterozygous or homozygous for or without the Phe232→Val variant (correcting for replicate effects), measured using a Click-iT protein synthesis assay (10). MFI correlates with methionine analog incorporation in nascent proteins. The P value indicates a nonzero effect of genotype from a linear regression of MFI on genotype and replicate. Red lines indicate means. (B) The Phe232→Val variant impairs iPSC proliferation in the homozygous but not heterozygous form. Results from a cell trace violet (CTV) proliferation assay, in which CTV concentration reduces on each division. The population of cells that have been through zero, one, or multiple divisions is labeled.

  • Fig. 4 KDM5B is a recessive DD gene in which heterozygous LOFs are incompletely penetrant.

    (A) Summary of damaging variants found in KDM5B. (B) Positions of likely damaging variants found in this and previous studies in KDM5B (ENST00000367264.2; introns not to scale), omitting two large deletions. Colors correspond to those shown in (A). There are no differences in the spatial distribution of LOFs by inheritance mode, nor in their likelihood of escaping nonsense-mediated decay by alternative splicing in GTex (28). (C to E) Behavioral defects of homozygous Kdm5b-null versus wild-type mice (n = 14 to 16 mice). (C) Knockout mice displayed increased anxiety, spending significantly less time in the light compartment of the light-dark box. (D) Reduced sociability, in the three-chamber sociability test. Knockout mice spent less time investigating a new mouse. (E) Twenty-four hour memory impairment. Whereas wild-type mice preferentially investigated an unfamiliar mouse over a familiar one, homozygous knockout mice showed no discrimination.

Supplementary Materials

  • Quantifying the contribution of recessive coding variation to developmental disorders

    Hilary C. Martin, Wendy D. Jones, Rebecca McIntyre, Gabriela Sanchez-Andrade, Mark Sanderson, James D. Stephenson, Carla P. Jones, Juliet Handsaker, Giuseppe Gallone, Michaela Bruntraeger, Jeremy F. McRae, Elena Prigmore, Patrick Short, Mari Niemi, Joanna Kaplanis, Elizabeth J. Radford, Nadia Akawi, Meena Balasubramanian, John Dean, Rachel Horton, Alice Hulbert, Diana S. Johnson, Katie Johnson, Dhavendra Kumar, Sally Ann Lynch, Sarju G. Mehta, Jenny Morton, Michael J. Parker, Miranda Splitt, Peter D Turnpenny, Pradeep C. Vasudevan, Michael Wright, Andrew Bassett, Sebastian S. Gerety, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles, Jeffrey C. Barrett, on behalf of the DDD Study

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

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    • Materials and Methods
    • Figs. S1 to S20
    • References
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