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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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.
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.
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. (PDF 2092 kb)
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). (MOV 4003 kb)
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). (MOV 3620 kb)
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). (MOV 3957 kb)
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). (MOV 3672 kb)
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). (MOV 716 kb)
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). (MOV 119 kb)
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Bilgüvar, K., Öztürk, A., Louvi, A. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207–210 (2010). https://doi.org/10.1038/nature09327
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