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 birth of neural progenitors in the peri-ventricular germinal zones, cell proliferation characterized by both symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in 6 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 development (MCD)3-6. Mapping of disease loci in putative Mendelian forms of MCD 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 WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with WDR62 mutations had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mouse and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. WDR62 expression 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 utility of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

“…These regions, which together comprised 27.16 MB, presumably contained the disease-causing mutation (Table S3). We next performed whole-exome sequencing of the index case using Nimblegen solid-phase array capture and the Illumina Genome Analyzer IIx instrument and focused on variants located within these shared regions (2)(3)(4)11). A single lane of sequencing on Illumina's Genome Analyzer IIX with single-read chemistry and a read length of 74 bases yielded ∼38 million reads.…”

Disease gene identification strategies for exome sequencing

“…Yamaguchi et al 56 Glazov et al 57 Puente et al 58 Gunay-Aygun et al 59 Weedon et al 60 Homozygosity (Figure 3b Becker et al 31 Walsh et al 35 Wang et al 51a Bolze et al 61 Caliskan et al 62 Bilguvar et al 63 O'Sullivan et al 64 Barak et al 65 Hanson et al 66 Shaheen et al 67 Doi et el Only a single experiment is required.…”

Small organelle, big responsibility: the role of centrosomes in development and disease

“…Therefore, in addition to balancing self-renewing and neurogenic divisions, the formation of the cortex requires neuronal migration. Although MCPH is widely believed to arise from abnormal neurogenesis, simplified gyral patterns have been reported in some cases, raising the possibility that neuronal migration defects occur in MCPH [12][13][14][15][16].…”