institutional review board approvals for genetic studies , along with written consent from all study subjects , were obtained at the participating institutions ( see supplementary notes ) . genomic dna of sample ng 26 - 1 was captured on a nimblegen 2.1 m human exome array with modifications to the manufacturer s protocol , followed by single - read cluster generation on the cluster station ( illumina , san diego , ca , usa ) . the captured , purified , and clonally amplified library targeting the exome from patient ng 26 - 1 two lanes of single - read sequencing at a read length of 74 base pairs was performed following the manufacturer s protocol . the sequence reads obtained were aligned to the human genome ( hg18 ) using maq and bwa   software . the percent alignment of the reads to both the reference genome as well as the targeted region , exome , was calculated using perl scripts . similarly , perl scripts were used for the detection of mismatch frequencies and error positions . samtools   was used for the detection of single nucleotide variations on the reads aligned with maq . the indels were detected on the reads aligned with bwa for its ability to allow for gaps during the alignment . shared homozygous segments of the affected individuals were detected using plink software version 1.06 , and the variants were filtered for shared homozygosity . the variants were annotated for novelty with comparison to both dbsnp ( build 130 ) and nine personal genome databases and previous exome sequencing experiments performed by our human genomics group . novel variants were further evaluated for their impact on the encoded protein , conservation across 44 vertebrate species and c. elegans and d. melanogaster , expression patterns and potential overlap with known mirnas . institutional review board approvals for genetic studies , along with written consent from all study subjects , were obtained at the participating institutions ( see supplementary notes ) . genomic dna of sample ng 26 - 1 was captured on a nimblegen 2.1 m human exome array with modifications to the manufacturer s protocol , followed by single - read cluster generation on the cluster station ( illumina , san diego , ca , usa ) . the captured , purified , and clonally amplified library targeting the exome from patient ng 26 - 1 was then sequenced on genome analyzer iix . two lanes of single - read sequencing at a read length of 74 base pairs was performed following the manufacturer s protocol . the sequence reads obtained were aligned to the human genome ( hg18 ) using maq and bwa   software . the percent alignment of the reads to both the reference genome as well as the targeted region , exome , was calculated using perl scripts . similarly , perl scripts were used for the detection of mismatch frequencies and error positions . samtools   was used for the detection of single nucleotide variations on the reads aligned with maq . the indels were detected on the reads aligned with bwa for its ability to allow for gaps during the alignment . shared homozygous segments of the affected individuals were detected using plink software version 1.06 , and the variants were filtered for shared homozygosity . the variants were annotated for novelty with comparison to both dbsnp ( build 130 ) and nine personal genome databases and previous exome sequencing experiments performed by our human genomics group . novel variants were further evaluated for their impact on the encoded protein , conservation across 44 vertebrate species and c. elegans and d. melanogaster , expression patterns and potential overlap with known mirnas .
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 .