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Case Reports
. 2011 Sep;155A(9):2071-7.
doi: 10.1002/ajmg.a.34165. Epub 2011 Aug 10.

Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria

David R Murdock  1 , Gary D Clark, Matthew N Bainbridge, Irene Newsham, Yuan-Qing Wu, Donna M Muzny, Sau Wai Cheung, Richard A Gibbs, Melissa B Ramocki
Affiliations
Case Reports

Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria

David R Murdock et al. Am J Med Genet A. 2011 Sep.

Abstract

Polymicrogyria is a disorder of neuronal development resulting in structurally abnormal cerebral hemispheres characterized by over-folding and abnormal lamination of the cerebral cortex. Polymicrogyria is frequently associated with severe neurologic deficits including intellectual disability, motor problems, and epilepsy. There are acquired and genetic causes of polymicrogyria, but most patients with a presumed genetic etiology lack a specific diagnosis. Here we report using whole-exome sequencing to identify compound heterozygous mutations in the WD repeat domain 62 (WDR62) gene as the cause of recurrent polymicrogyria in a sibling pair. Sanger sequencing confirmed that the siblings both inherited 1-bp (maternal allele) and 2-bp (paternal allele) frameshift deletions, which predict premature truncation of WDR62, a protein that has a role in early cortical development. The probands are from a non-consanguineous family of Northern European descent, suggesting that autosomal recessive PMG due to compound heterozygous mutation of WDR62 might be a relatively common cause of PMG in the population. Further studies to identify mutation frequency in the population are needed.

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Figures

FIG. 1
FIG. 1
Magnetic resonance imaging of the head in patients II-1 (A–C) and II-2 (D–F). A: Sagittal T1 image demonstrates microcephaly and an abnormal corpus callosum (depicted by white arrows). B: Axial T2 and [C] coronal T1 images demonstrate bilateral parietal polymicrogyria and an abnormal sulcal and gyral pattern. Patient II-2: D: Sagittal T1 image demonstrates overall preservation of midline structures. E: Axial T1 and (F) coronal T2 images demonstrate extensive polymicrogyria in the left cerebral hemisphere. White arrows in panels B, C, E, and F depict regions of polymicrogyria. G: Pedigree with Sanger traces below demonstrating WDR62 mutation family segregation. The affected patients (black squares) inherited both the maternal c.2083delA and paternal c.2472_2473delAG alleles. In the traces, black arrows show the beginning of each deletion. Following each heterozygous deletion there are overlapping traces representing the wild-type and shifted sequences. [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552–4833]
FIG. 2
FIG. 2
A: Sequence alignment visualization showing heterozygous WDR62 mutations in both patient II-1 (upper panel) and patient II-2 (lower panel). Individual sequencing reads are represented by the horizontal grey bars. Both c.2083delA and c.2472_2473delAG deletions are present in approximately half of each patient’s reads, representing a heterozygous state for each mutation. Alignment also shows heterozygous missense variants in (B) GLI2 and (C) KIAA1598 in patient II-1 but not in patient II-2. [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552–4833]
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