Abstract

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers1,2. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development3,4,5,6. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

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Acknowledgements

We are indebted to the patients and families who have contributed to this study. We thank J. Noonan for expert advice and C. Camputaro for her help with three-dimensional reconstruction of the magnetic resonance images. This study was supported by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, and National Institutes of Health grants RC2 NS070477 (to M.G.), UL1 RR024139NIH (Yale Clinical and Translational Science Award) and UO1MH081896 (to N.S.). SNP genotyping was supported in part by a National Institutes of Health Neuroscience Microarray Consortium award U24 NS051869-02S1 (to S.M.). R.P.L. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Kaya Bilgüvar
    •  & Ali Kemal Öztürk

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Kaya Bilgüvar
    • , Ali Kemal Öztürk
    • , Angeliki Louvi
    • , Tanyeri Barak
    • , Mehmet Bakırcıoğlu
    • , Katsuhito Yasuno
    • , Winson Ho
    • , Michele H. Johnson
    • , Richard A. Bronen
    •  & Murat Günel
  2. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Kaya Bilgüvar
    • , Ali Kemal Öztürk
    • , Angeliki Louvi
    • , Kenneth Y. Kwan
    • , Tanyeri Barak
    • , Mehmet Bakırcıoğlu
    • , Katsuhito Yasuno
    • , Winson Ho
    • , Ying Zhu
    • , Nenad Šestan
    •  & Murat Günel
  3. Department of Genetics, Center for Human Genetics and Genomics and Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Kaya Bilgüvar
    • , Ali Kemal Öztürk
    • , Angeliki Louvi
    • , Murim Choi
    • , Tanyeri Barak
    • , Mehmet Bakırcıoğlu
    • , Katsuhito Yasuno
    • , Winson Ho
    • , Stephan Sanders
    • , Shrikant Mane
    • , Richard P. Lifton
    • , Matthew W. State
    •  & Murat Günel
  4. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Kenneth Y. Kwan
    • , Ying Zhu
    •  & Nenad Šestan
  5. Division of Neurology, Department of Pediatrics, Istanbul University Istanbul Medical Faculty, Istanbul 34093, Turkey

    • Burak Tatlı
    •  & Meral Özmen
  6. Division of Neurology, Department of Pediatrics, Hacettepe University School of Medicine, Sihhiye, Ankara 06100, Turkey

    • Dilek Yalnızoğlu
    •  & Meral Topçu
  7. Division of Genetics, Department of Pediatrics, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul 34098, Turkey

    • Beyhan Tüysüz
  8. Department of Medical Genetics, Kayseri Education and Research Hospital, Kayseri 38010, Turkey

    • Ahmet Okay Çağlayan
  9. Division of Neurology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir 35100, Turkey

    • Sarenur Gökben
    •  & Sanem Yılmaz
  10. Faculty of Arts and Sciences, Bahcesehir University, Istanbul 34353, Turkey

    • Hande Kaymakçalan
  11. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Stephan Sanders
    •  & Matthew W. State
  12. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Stephan Sanders
    •  & Matthew W. State
  13. Department of Radiology, Acibadem University School of Medicine, Istanbul 34742, Turkey

    • Alp Dinçer
  14. Department of Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Michele H. Johnson
    •  & Richard A. Bronen
  15. Department of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Michele H. Johnson
  16. Department of Radiology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul 34098, Turkey

    • Naci Koçer
  17. Division of Neurology, Department of Pediatrics, Erciyes University School of Medicine, Kayseri 38039, Turkey

    • Hüseyin Per
    •  & Sefer Kumandaş
  18. Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Shrikant Mane
  19. Department of Neurosurgery, Acibadem University School of Medicine, Istanbul 34742, Turkey

    • Mehmet Necmettin Pamir
  20. Division of Child Neurology, Department of Neurology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul 34098, Turkey

    • Cengiz Yalçınkaya
  21. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Richard P. Lifton

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Contributions

M.W.S., R.P.L. and M.G. designed the study and K.B., A.L., N.S., R.P.L. and M.G. designed the experiments. K.B., A.K.O., A.L., K.Y.K., T.B., M.B., S.S., W.H. and S.M. performed the experiments. B.T., D.Y., B.T., A.O.C., S.G., H.K., S.Y., H.P., C.Y., S.K., M.T. and M.O. identified, consented and recruited the study subjects and provided clinical information. A.D., M.H.J., R.A.B., N.K. and M.N.P. performed and evaluated magnetic resonance imaging. M.C. and R.P.L. developed the bioinformatics scripts for data analysis. K.B., A.K.O., K.Y., A.L. and M.G. analysed the genetics data. A.L., K.Y.K, Y.Z., N.S. and M.G. analysed the expression data. K.B., A.K.O, A.L., R.P.L., M.W.S. and M.G. wrote the paper.

Competing interests

The authors have a provisional patent application under consideration based on the findings of this work. R.A.B. is a consultant for Bristol-Myers Squibb.

Corresponding authors

Correspondence to Richard P. Lifton or Matthew W. State or Murat Günel.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Patient Notes, legends for Supplementary Videos 1- 6 (see separate Movie files 1-6), Supplementary Figures 1-8 with legends and Supplementary Tables 1-6.

Videos

  1. 1.

    Supplementary Movie 1

    This video is constructed from T2 sagittal images (photographically inverted) of patient NG 26-1 and demonstrates microcephaly and cortical thickening (see Supplementary Information file for full legend).

  2. 2.

    Supplementary Movie 2

    This video is constructed from T2 coronal images (photographically inverted) of patient NG 26-1 and demonstrates microcephaly and cortical thickening (see Supplementary Information file for full legend).

  3. 3.

    Supplementary Movie 3

    This video is constructed from T2 sagittal images of patient NG 190-1 (photographically inverted) and it shows diffuse cortical volume loss and marked craniofacial disproportion (see Supplementary Information file for full legend).

  4. 4.

    Supplementary Movie 4

    This video is constructed from T2 coronal images of patient NG 190-1 (photographically inverted) and it shows diffuse cortical volume loss and marked craniofacial disproportion (see Supplementary Information file for full legend).

  5. 5.

    Supplementary Movie 5

    This video is constructed from T1 sagittal images (photographically inverted) of patient NG 891-1 and it demonstrates radiographic findings consistent with microlissencephaly including prominent microcephaly (see Supplementary Information file for full legend).

  6. 6.

    Supplementary Movie 6

    This video is constructed from T1 coronal images (photographically inverted) of patient NG 891-1 and it demonstrates radiographic findings consistent with microlissencephaly including prominent microcephaly (see Supplementary Information file for full legend).

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DOI

https://doi.org/10.1038/nature09327

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