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Case Reports
. 2016 Aug 23;4(10):952-956.
doi: 10.1002/ccr3.663. eCollection 2016 Oct.

Activation of an Exonic Splice-Donor Site in Exon 30 of CDK5RAP2 in a Patient With Severe Microcephaly and Pigmentary Abnormalities

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Free PMC article
Case Reports

Activation of an Exonic Splice-Donor Site in Exon 30 of CDK5RAP2 in a Patient With Severe Microcephaly and Pigmentary Abnormalities

Alistair T Pagnamenta et al. Clin Case Rep. .
Free PMC article

Abstract

This report constitutes the first report of a cryptic exonic splice-donor site in CDK5RAP2, highlights the importance of evaluating novel splice mutations, and suggests that the phenotypic range associated with CDK5RAP2 mutations may include skin pigmentary abnormalities.

Keywords: CDK5RAP2; exome; exonic splice‐donor; microcephaly; pigmentation abnormalities.

Figures

Figure 1
Figure 1
Clinical images showing microcephaly and pigmentation anomalies. (A) Photograph showing the small head size (−5 to −6 SD), sloping forehead, and prominent nose. (B, C) Arrows indicate the multiple café au lait patches. (D) MRI brain scan (sagittal view) showing a small brain with normal corpus callosum.
Figure 2
Figure 2
Analysis of the CDK5RAP2 mutations at the RNA level. (A) Bioanalyzer image showing a 371‐bp product as expected for the exon 28–31 RTPCR product. A lower band was also observed for BRC081 and his mother, consistent with the 342‐bp product predicted by MaxEntScan algorithm. A similar pattern was also seen using the smaller exon 29–31 RTPCR product (data not shown). Relative quantification of RTPCR products is shown in Table S3. (B) Sanger sequencing of the exon 28–31 RTPCR product confirmed the use of a cryptic splice‐donor site in the patient, 29 bp upstream of the usual splice site. The sequence for the frameshifted transcript is weaker in the mother than it is for BRC081 (where both chromosomes carry LoF mutations). This observation is consistent with the relative band intensities seen in panel (A). The position of the 31R primer is shown with an arrow. (C) Sanger sequencing of the exon 22–24 RTPCR product confirms that the c.3097delG transcript is also expressed. Again, the sequence for the frameshifted transcript is slightly weaker in the father than it is for BRC081 (where both chromosomes carry LoF mutations).

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References

    1. Bond J., Roberts E., Springell K., Lizarraga S. B., Scott S., Higgins J., et al. 2005. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet. 37:353–355. - PubMed
    1. Yigit G., Brown K. E., Kayserili H., Pohl E., Caliebe A., Zahnleiter D., et al. 2015. Mutations in CDK5RAP2 cause Seckel syndrome. Mol. Genet. Genomic Med. 3:467–480. - PMC - PubMed
    1. Jouan L., Ouled Amar Bencheikh B., Daoud H., Dionne‐Laporte A., Dobrzeniecka S., Spiegelman D., et al. 2015. Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum. Eur. J. Hum. Genet. 24:607–610. - PMC - PubMed
    1. Kim T., Park J. S., Lee P., Jin Y., Fu S. B., Rosales J. L., et al. 2011. Novel alternatively spliced variant form of human CDK5RAP2 . Cell Cycle 10:1010–1012. - PMC - PubMed
    1. Tan C. A., Topper S., Ward Melver C., Stein J., Reeder A., Arndt K., et al. 2014. The first case of CDK5RAP2‐related primary microcephaly in a non‐consanguineous patient identified by next generation sequencing. Brain Dev. 36:351–355. - PubMed

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