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KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant


Copy number variants (CNVs) are major contributors to genetic disorders1. We have dissected a region of the 16p11.2 chromosome—which encompasses 29 genes—that confers susceptibility to neurocognitive defects when deleted or duplicated2,3. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication2,3,4,5, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion5,6, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.

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Figure 1: Systematic analysis of 16p11.2 deletion or duplication genes in vivo induces defects in head size.
Figure 2: KCTD13 dosage changes lead to head size, proliferation and apoptosis defects.
Figure 3: KCTD13 dosage changes lead to neuroanatomical defects.
Figure 4: Kctd13 regulates mammalian cell proliferation in vitro and in vivo.


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We thank C. Hanscom for technical assistance. We also thank J. Black, J. Whetstine, K. Brown and C. Lee for assistance with the initial and confirmatory array CGH experiments, S. Santagelo for analysis of clinical phenotype data, and M. State, M. Daley and R. Gibbs for sharing unpublished exome sequencing data. This work was supported by a Silvo O. Conte center grant (MH-094268) from the National Institute of Mental Health (NIMH), National Institutes of Health grant MH-084018 (A.S., A.K. and N.K.), grant MH-091230 (A.K.), grant HD06286 (J.F.G.), the Simon's Foundation, the Autism Consortium of Boston (J.F.G.), the Leenaards Foundation Prize (S.J. and A.R.), the Swiss National Science Foundation (A.R. and J.S.B.), a Swiss National Science Foundation Sinergia grant (S.J., J.S.B. and A.R.). M.E.T. was supported by an NIMH National Research Service Award (F32MH087123). S.J. is a recipient of a bourse de relève académique de la Faculté de Biologie et Médecine de l’Université de Lausanne. N.K. is a Distinguished Brumley Professor.

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Author Contributions C.G. and N.K. designed the study and wrote the paper, and all authors approved and commented on the manuscript. C.G. performed the zebrafish studies, immunostaining, TUNEL and sectioning experiments, and counting analyses. J.W. made the plasmid constructs and capped mRNAs. M.E.T., M.S. and J.F.G. performed the human genetic analyses. E.C.O. performed the shRNA silencing and BrdU pulse experiments, and generated mice brain sections. Y.T., A.S. and A.K. performed in utero electroporations. S.J., A.R. and J.S.B. designed the 16p-specific microarray and shared unpublished data that informed our experimental design.

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Correspondence to Nicholas Katsanis.

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Golzio, C., Willer, J., Talkowski, M. et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485, 363–367 (2012).

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