Whole exome sequencing — a new gene scanning technology that cuts the cost and time of searching for rare mutations — can identify mutations in a single gene that can cause several types of developmental brain abnormalities that have traditionally been considered different disorders, according to a study published online Aug 22 in Nature.
Murat Gunel, MD, chief of the neurovascular surgery program and co-director of the program on neurogenetics at Yale University in New Haven, Conn., and colleagues conducted the study to “identify disease loci in settings in which traditional methods have proved challenging."
The research was funded in part by a $2.9 million stimulus grant from the National Institutes of Health’s (NIH) National Institute of Neurological Disorders and Stroke (NINDS), made available through the American Recovery and Reinvestment Act (ARRA).
“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,” wrote the researchers. Thus far, they noted that disease mapping within genes of mutations in cortical development has been hindered by marked locus heterogeneity, small population sizes and diagnostic classifications that may not reflect molecular pathogenesis.
The authors focused on children with malformations of cortical development (MCD) for their research. Gunel and his colleagues worked with researchers in Turkey to study Turkish families with MCD, as the highest incidence of MCD is among children born to parents who are related and Turkey has a tradition of first- and second-cousin marriages.
The researchers studied two related children who were diagnosed with microcephaly. Whole exome sequencing revealed mutations in the WDR62 gene in both children. Next, the researchers included children from other families diagnosed with microcephaly who also had WDR62 gene mutations. Within 30 included families, six unique mutations in the WDR62 gene were identified by the authors.
Through the gene scanning method, the authors were able to identify recessive mutations in 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,” wrote the authors.
Gunel and colleagues concluded that information provided by exome sequencing can help couples assess the risk of passing on genetic disorders to their children, as well as disease mechanisms and treatments. The researchers plan to further their research by way of their ARRA grant to extend the scanning technique to hundreds of additional families with MCD, as well to investigate the functions of WDR62 in mouse studies.