對與異常皮層發(fā)育相關的基因位點的識別,，因遺傳異質性、小家庭規(guī)模和不能反映分子發(fā)病機制的診斷分類而復雜化,。
這些障礙在一項采用“全外顯子組”(whole-exome)測序方法的研究中已被克服,。在“WD重復區(qū)域-62” (WDR62)基因上所發(fā)生的隱性突變，被發(fā)現(xiàn)引起一系列看起來迥然不同的腦異常,，包括小頭癥,、巨腦回和小腦發(fā)育不良（在一例中發(fā)現(xiàn)有這種異常）。
與其他已知的小頭癥基因不同的是,，WDR62不與中心體結合,；它從位置上來講主要在細胞核中,，并且在胚胎神經(jīng)發(fā)生過程中在新皮層中瞬時表達。（生物谷Bioon.com）
生物谷推薦英文摘要：
Nature doi:10.1038/nature09327
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
Kaya Bilgüvar,Ali Kemal ?ztürk,Angeliki Louvi,Kenneth Y. Kwan,Murim Choi,Burak Tatl?,Dilek Yaln?zo?lu,Beyhan Tüysüz,Ahmet Okay ?a?layan,Sarenur G?kben,Hande Kaymak?alan,Tanyeri Barak,Mehmet Bak?rc?o?lu,Katsuhito Yasuno,Winson Ho,Stephan Sanders,Ying Zhu,Sanem Y?lmaz,Alp Din?er,Michele H. Johnson,Richard A. Bronen,Naci Ko?er,Hüseyin Per,Shrikant Mane,Mehmet Necmettin Pamir,Cengiz Yal??nkaya,Sefer Kumanda?,Meral Top?u,Meral ?zmen,Nenad ?estan,Richard P. Lifton,[email protected] W. [email protected]& Murat Günel
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.
