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.
Bilgüvar
Kaya
K
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Oztürk
Ali Kemal
AK
Louvi
Angeliki
A
Kwan
Kenneth Y
KY
Choi
Murim
M
Tatli
Burak
B
Yalnizoğlu
Dilek
D
Tüysüz
Beyhan
B
Cağlayan
Ahmet Okay
AO
Gökben
Sarenur
S
Kaymakçalan
Hande
H
Barak
Tanyeri
T
Bakircioğlu
Mehmet
M
Yasuno
Katsuhito
K
Ho
Winson
W
Sanders
Stephan
S
Zhu
Ying
Y
Yilmaz
Sanem
S
Dinçer
Alp
A
Johnson
Michele H
MH
Bronen
Richard A
RA
Koçer
Naci
N
Per
Hüseyin
H
Mane
Shrikant
S
Pamir
Mehmet Necmettin
MN
Yalçinkaya
Cengiz
C
Kumandaş
Sefer
S
Topçu
Meral
M
Ozmen
Meral
M
Sestan
Nenad
N
Lifton
Richard P
RP
State
Matthew W
MW
Günel
Murat
M
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human