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

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