Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture


Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat–containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.

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Figure 1: Pedigrees and radiographic findings in six consanguineous families with MCSG.
Figure 2: Mapping, capture and sequencing of 148 genes in the MCSG locus.
Figure 3: Six WDR62 mutations reported in association with microcephaly with simplified gyri.
Figure 4: WDR62 expression in developing mouse brain and subcellular localization.
Figure 5: Histopathologic analysis of a 27-week-old human fetus with MCSG.

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We thank the many families and researchers who participated in this study; B. Chang and A. Poduri for expert review of MRI imaging findings; S. Lizarraga for contributions to genetic mapping; M. Aita and the In situ Hybridization Core Facility, University of North Carolina Neuroscience Center, Chapel Hill, North Carolina for performing in situ hybridizations; C.G. Woods for helpful discussions and for sharing data before publication; A. von Deimling from the Institut für Pathologie, Heidelberg, for sectioning of the LIS-2601 brain; A. Nicholas and M. Khurshid for advice regarding immunohistochemistry; A. Hill and L. Bu at the MRDDRC (Mental Retardation Developmental Disability Research Center) Imaging Core for assistance with confocal microscopy (US National Institutes of Health (NIH) grant P30-HD-18655 and Fidelity Foundation); and R. Sean Hill for assistance with linkage analysis and helpful discussions. We are indebted to the members of the Microcephaly Collaborative (Supplementary Table 1) for contributing to the cohort from which these families were drawn. T.W.Y. was supported by a NIH T32 grant (T32 NS007484-08), the Clinical Investigator Training Program (CITP) at Harvard-Massachusetts Institute of Technology Health Sciences and Technology and Beth Israel Deaconess Medical Center in collaboration with Pfizer, Inc. and Merck and Company, Inc., and the Nancy Lurie Marks Junior Faculty MeRIT Fellowship. G.H.M. was supported by the Young Investigator Award of National Alliance for Research on Schizophrenia and Depression (NARSAD) as a NARSAD Lieber Investigator. Research was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (RO1 NSR01-35129) and the Fogarty International Center (R21 NS061772) to C.A.W., the Dubai Harvard Foundation for Medical Research and the Manton Center for Orphan Disease Research. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to Johns Hopkins University, contract number HHSN268200782096C and NIH N01-HG-65403. Genotyping at Children's Hospital Boston was supported by the Intellectual and Developmental Disabilities Research Centers (CHB DDRC, P30 HD18655). Genotyping at the Broad Institute was supported by National Human Genome Research Institute (NHGRI). C.A.W. is an investigator of the Howard Hughes Medical Institute.

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T.W.Y. helped characterize MCSG syndrome, designed and performed targeted capture experiments, generated sequencing libraries, designed bioinformatics pipelines, analyzed sequencing data, identified WDR62 mutations, designed WDR62 in situ expression studies, designed, performed and analyzed WDR62 immunohistochemistry studies, helped analyze the LIS-2601 postmortem specimen and wrote the manuscript. G.H.M. helped characterize MCSG syndrome, performed initial genome wide linkage studies and identified the MCSG locus. D.J.T. designed and performed WDR62 immunohistochemistry studies, helped analyze in situ expression studies and helped analyze the LIS-2601 postmortem specimen. S.K.S. helped characterize MCSG syndrome, identified additional affected families, analyzed SNP and microsatellite genotyping and narrowed the MCSG genomic interval. L.F.-S. helped characterize MCSG syndrome and wrote the initial clinical description of the LIS-900 family. C.M.S. identified the LIS-2600 family and provided clinical information and the LIS-2601 postmortem specimen. M.T. identified the MC-1400 and MC-1600 families and provided clinical information. M.T.M. identified the PH-16900 family and provided clinical information. B.J.B. organized clinical information and subject samples. J.M.F. sequenced WDR62 in families to confirm high throughput sequencing findings and to discover additional alleles. C.S. helped with bioinformatic pipelines and generated constructs for WDR62 in situ expression studies. W.B.D. referred the PH-16900 family. R.D.F. analyzed the LIS-2601 postmortem specimen. A.J.B. reviewed MRIs for characterization of MCSG syndrome. C.A.W. directed the overall research, helped analyze the LIS-2601 postmortem specimen and wrote the manuscript.

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Correspondence to Christopher A Walsh.

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Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–4 and Supplementary Table 1 (PDF 2835 kb)

Microcephaly, simplified gyri, polymicrogyria, and schizencephaly in a patient with a WDR62 mutation. T1-weighted MRI sequence of a patient (PH-16903) with a homozygous V65M mutation, demonstrating microcephaly, simplified gyri, relatively preserved brain stem and cerebellum, widespread polymicrogyria, and right temporo-parietal open lip schizencephaly. (MOV 464 kb)

Supplementary Movie 1

Microcephaly, simplified gyri, polymicrogyria, and schizencephaly in a patient with a WDR62 mutation. T1-weighted MRI sequence of a patient (PH-16903) with a homozygous V65M mutation, demonstrating microcephaly, simplified gyri, relatively preserved brain stem and cerebellum, widespread polymicrogyria, and right temporo-parietal open lip schizencephaly. (MOV 464 kb)

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Yu, T., Mochida, G., Tischfield, D. et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42, 1015–1020 (2010).

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