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

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.

The Carotid Endarterectomy Cadaveric Investigation for Cranial Nerve Injuries: Anatomical Study.

Cerebral stroke continues to be one of the leading causes of mortality and long-term morbidity; therefore, carotid endarterectomy (CEA) remains to be a popular treatment for both symptomatic and asymptomatic patients with carotid stenosis. Cranial nerve injuries remain one of the major contributor to the postoperative morbidities. Anatomical dissections were carried out on 44 sides of 22 cadaveric heads following the classical CEA procedure to investigate the variations of the local anatomy as a contributing factor to cranial nerve injuries. Concurrence of two variations was found to be important in hypoglossal nerve injury: the presence of a direct smaller vein in proximity of the carotid bifurcation, and the intersection of the hypoglossal nerve (HN) with this vein. Based on the sample investigated, this variation was observed significantly higher on the right side. Awareness of possible anatomical variations and early ligation of any small veins can significantly decrease iatrogenic injury risk.