, Volume 10, Issue 3, pp 241–250 | Cite as

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

  • S. Russo
  • M. Marchi
  • F. Cogliati
  • M. T. Bonati
  • M. Pintaudi
  • E. Veneselli
  • V. Saletti
  • M. Balestrini
  • B. Ben-Zeev
  • L. Larizza
Original Article


It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T > C p.Ile72Thr and c.380A > G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145 + 2 T > C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.


Mutation screening RNA analysis Genotype–phenotype correlation 



We thank A.I.R. (Associazione Italiana Rett) for support of this study by a dedicated grant and for making available their daughters' samples and Galliera Genetic Bank for establishment of lymphoblastoid cell lines. This study was supported by the European grant E-Rare JTC 2007 (to S.R.) entitled European Network on Rett Syndrome.

Supplementary material

10048_2009_177_MOESM1_ESM.xls (17 kb)
Supplementary Table 2 (XLS 17 KB)
10048_2009_177_Fig1_ESM.gif (220 kb)
Supplementary Fig. 6

Electropherogram of the splicing mutation affecting IVS16 carried by patient 7 and spliceview analysis, which predicts splicing consensus abolition (GIF 219 KB)

10048_2009_177_Fig1_ESM.tif (131 kb)
High resolution (TIFF 131 KB)


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • S. Russo
    • 1
  • M. Marchi
    • 1
  • F. Cogliati
    • 1
  • M. T. Bonati
    • 1
  • M. Pintaudi
    • 2
  • E. Veneselli
    • 2
  • V. Saletti
    • 3
  • M. Balestrini
    • 3
  • B. Ben-Zeev
    • 4
  • L. Larizza
    • 1
    • 5
  1. 1.Molecular Genetics LaboratoryIstituto Auxologico ItalianoMilanItaly
  2. 2.Department of Child Neuropsychiatry, G. Gaslini HospitalUniversity of GenoaGenoaItaly
  3. 3.Unit of Developmental NeurologyIstituto Neurologico Carlo BestaMilanItaly
  4. 4.Sheba Med. CtrRamat-GanIsrael
  5. 5.Division of Medical Genetics, San Paolo School of MedicineUniversity of MilanMilanItaly

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