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Case Reports
. 2014 Jul 22:7:465.
doi: 10.1186/1756-0500-7-465.

Whole-exome sequencing identifies a de novo TUBA1A mutation in a patient with sporadic malformations of cortical development: a case report

Keiko Shimojima, Aya Narita, Yoshihiro Maegaki, Akira Saito, Toru Furukawa, Toshiyuki Yamamoto  1
Affiliations
Case Reports

Whole-exome sequencing identifies a de novo TUBA1A mutation in a patient with sporadic malformations of cortical development: a case report

Keiko Shimojima et al. BMC Res Notes. .

Abstract

Background: Owing to the number of genetic mutations that contribute to malformations of cortical development, identification of causative mutations in candidate genes is challenging. To overcome these challenges, we performed whole-exome sequencing in this study.

Case presentation: A Japanese patient presented with microcephaly and severe developmental delay. Brain magnetic resonance imaging showed the presence of colpocephaly associated with lateral ventricle dilatation and the presence of a simplified gyral pattern. Hypoplasia of the corpus callosum and cerebellar vermis were also noted. Because Sanger sequencing is expensive, laborious, and time-consuming, whole-exome sequencing was performed and a de novo missense mutation in TUBA1A (E27Q) was identified.

Conclusion: The novel mutation identified in this study was located in the genetic region that encodes the N-terminal domain of TUBA1A, a region of TUBA1A with few reported mutations. Retrospective assessment of the clinical and radiological features of this patient-i.e., microcephaly, lissencephaly (pachygyria) with cerebellar hypoplasia, and corpus callosum hypoplasia-indicated that the TUBA1A mutation did not lead to any contradictions. Because rapid and comprehensive mutation analysis by whole-exome sequencing is time- and cost-effective, it might be useful for genetic counseling of patients with sporadic malformations of cortical development.

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Figures

Figure 1
Figure 1
Brain magnetic resonance imaging of the patient. T2-weighted sagittal (A) and T1-weighted axial (B) images at 6 days after birth indicate hypoplastic vermis of the cerebellum, cortical dysgenesis with a simplified gyral pattern, and dilatation of the lateral ventricles. T1-weighted (C and E) and T2-weighted (D and F) axial images at 3 months of age indicate colpocephalic appearance associated with dilatation of the lateral ventricles. Cortical gyration is poor and reduced volume of the white matter is apparent.
Figure 2
Figure 2
Flow chart indicating the validation process for variants. After 5 steps of validation, 16 genetic variants are finally selected.
Figure 3
Figure 3
Results of Sanger sequencing and a map of the identified mutation locus. (A) A Sanger sequencing electropherogram identifying the missense mutation, c.79G > C (E27Q), is shown. (B) A genome map of the locus surrounding the mutation captured from the UCSC genome browser is depicted. Because TUBA1A is encoded in an antisense manner, the reverse-complement nucleotide sequence is shown. The affected amino acid is indicated by a red rectangle. The c.79C residue is conserved among many species as shown.
See this image and copyright information in PMC

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