Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

Kaya Bilgüvar, Ali Kemal Öztürk, Angeliki Louvi, Kenneth Y. Kwan, Murim Choi, Burak Tatli, Dilek Yalnizoǧlu, Beyhan Tüysüz, Ahmet Okay Çaǧlayan, Sarenur Gökben, Hande Kaymakçalan, Tanyeri Barak, Mehmet Bakircioǧlu, Katsuhito Yasuno, Winson Ho, Stephan Sanders, Ying Zhu, Sanem Yilmaz, Alp Dinçer, Michele H. JohnsonRichard A. Bronen, Naci Koçer, Hüseyin Per, Shrikant Mane, Mehmet Necmettin Pamir, Cengiz Yalçinkaya, Sefer Kumandaş, Meral Topçu, Meral Özmen, Nenad Šestan, Richard P. Lifton, Matthew W. State, Murat Günel

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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 development3-6. 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.

Original languageEnglish
Pages (from-to)207-210
Number of pages4
Issue number7312
StatePublished - 9 Sep 2010

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Bilgüvar, K., Öztürk, A. K., Louvi, A., Kwan, K. Y., Choi, M., Tatli, B., Yalnizoǧlu, D., Tüysüz, B., Çaǧlayan, A. O., Gökben, S., Kaymakçalan, H., Barak, T., Bakircioǧlu, M., Yasuno, K., Ho, W., Sanders, S., Zhu, Y., Yilmaz, S., Dinçer, A., ... Günel, M. (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467(7312), 207-210. https://doi.org/10.1038/nature09327