title: Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.
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 layers. 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 development. 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.
authors: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Kaya
authors: K
authors: Bilgüvar
authors: Ali Kemal
authors: AK
authors: Oztürk
authors: Angeliki
authors: A
authors: Louvi
authors: Kenneth Y
authors: KY
authors: Kwan
authors: Murim
authors: M
authors: Choi
authors: Burak
authors: B
authors: Tatli
authors: Dilek
authors: D
authors: Yalnizoğlu
authors: Beyhan
authors: B
authors: Tüysüz
authors: Ahmet Okay
authors: AO
authors: Cağlayan
authors: Sarenur
authors: S
authors: Gökben
authors: Hande
authors: H
authors: Kaymakçalan
authors: Tanyeri
authors: T
authors: Barak
authors: Mehmet
authors: M
authors: Bakircioğlu
authors: Katsuhito
authors: K
authors: Yasuno
authors: Winson
authors: W
authors: Ho
authors: Stephan
authors: S
authors: Sanders
authors: Ying
authors: Y
authors: Zhu
authors: Sanem
authors: S
authors: Yilmaz
authors: Alp
authors: A
authors: Dinçer
authors: Michele H
authors: MH
authors: Johnson
authors: Richard A
authors: RA
authors: Bronen
authors: Naci
authors: N
authors: Koçer
authors: Hüseyin
authors: H
authors: Per
authors: Shrikant
authors: S
authors: Mane
authors: Mehmet Necmettin
authors: MN
authors: Pamir
authors: Cengiz
authors: C
authors: Yalçinkaya
authors: Sefer
authors: S
authors: Kumandaş
authors: Meral
authors: M
authors: Topçu
authors: Meral
authors: M
authors: Ozmen
authors: Nenad
authors: N
authors: Sestan
authors: Richard P
authors: RP
authors: Lifton
authors: Matthew W
authors: MW
authors: State
authors: Murat
authors: M
authors: Günel
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human