Novel Mutation chrX:110644366 C>A of the DCX Gene in 4-year-old Girl with Sporadic Double Cortex Syndrome

Natalia A. Shnayder, PhD, ScD¹*; Ivan P. Artyukhov, PhD, ScD¹; Ekaterina V. Egorova¹; Diana V. Dmitrienko, PhD, ScD¹; Olga S. Shilkina¹; Alexander A. Molgachev²

¹V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, ²S.M. Berezin Medical-Diagnostics Center of the International Institute of Biological Systems; Krasnoyarsk, the Russian Federation

*Corresponding authorProf. Natalia A. Shnayder, PhD, ScD; Head of the Neurological Center of Epileptology, Neurogenetics and Brain Research of the University Clinic of V.F. Voino-Yasenetsky Krasnoyarsk State Medical University;  Krasnoyarsk, the Russian Federation.  E-mail:

Published: March 17, 2017.  doi: 10.21103/Article7(1)_CR2


Subcortical band heterotopia (SBH), also known as double cortex syndrome (DC), is listed as a "rare disease" by the Genetic and Rare Diseases Information Center of the National Institutes of Health with an incidence of 1 to 200,000 people in the population.  The cause of the disease is mutation in the DCX gene (also known as DBCN, XLIS) on chromosome Xq22.3-q23. SBH is an X-linked dominant disorder. Traditionally, genetic testing for SBH has been done in the order of the probability of detection of mutation according to the radiologic features, but the success rate could be variable with this time-consuming approach.
In this study, novel mutation chrX: 110644366C>A in the DCX gene was identified in a 4-year-old Russian girl with sporadic SBH. The present report demonstrates that whole-exome sequencing may be a useful tool for the identification of previously known and de novo mutations in children with SBH as well as malformations of cortical development.

Double cortex syndrome ● absence seizures ● DCX gene ● de novo mutations
  1. Couillard-Despres S, Winkler J, Uyanik G, Aigner L. Molecular mechanisms of neuronal migration disorders, quovadis? Curr Mol Med. 2001;1(6):677–88.
  2. Couillard-Despres S, Uyanik G, Ploetz S, Karl C, Koch H, Winkler J, Aigner L. Mitotic impairment by doublecortin mutations found in patients. Neurogenetics. 2004;5(2):83-93.
  3. Bahi-Buisson N1, Souville I, Fourniol FJ, Toussaint A, Moores CA, Houdusse A, et al. New insights into genotype–phenotype correlations for the doublecortin-related lissencephaly spectrum. Brain. 2013;136(Pt 1): 223–44. doi: 10.1093/brain/aws323.
  4. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92(1):63-72.
  5. des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrié A, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998;92(1):51-61.
  6. Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA, Wolf SG, et al. Doublecortin mutations cluster in evolutionarily conserved functional domains. Hum Mol Genet. 2000;9(5):703-12.
  7. des Portes V, Francis F, Pinard JM, Desguerre I, Moutard ML, Snoeck I, et al. Doublecortin is the major gene causing X-linked subcortical laminar heterotopias (SHLH). Hum Mol Genet. 1998;7(7):1063–70.
  8. Dobyns WB, Andermann E, Andermann F, Czapansky-Beilman D, Dubeau F, Dulac O, et al. X-linked malformations of neuronal migration. Neurology. 1996;47(2):331–9.
  9. Ross ME, Allen KM, Srivastava AK, Featherstone T, Gleeson JG, Hirsch B, et al. Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain. Hum Mol Genet. 1997;6(4):555–62.
  10. Palmini A, Andermann F, Aicardi J, Dulac O, Chaves F, Ponsot G, et al. Diffuse cortical dysplasia, or the “double cortex” syndrome: the clinical and epileptic spectrum in 10 patients. Neurology. 1991;41(10):1656–62.
  11. Granata T, Battaglia G, D'Incerti L, Franceschetti S, Zucca C, Savoiardo M, Avanzini G. Double cortex syndrome: electroclinical study of three cases. Ital J Neurol Sci. 1994;15(1):15–23.
  12. Parmeggiani A, Santucci M, Ambrosetto P, Amadi A, Baioni E, Rossi PG. Interictal EEG findings in two cases with “double cortex”syndrome. Brain Dev. 1994;16(4):320–4.
  13. Ricci S, Cusmai R, Fariello G, Fusco L, Vigevano F. Double cortex. A neuronal migration anomaly as a possible cause of Lennox-Gastaut syndrome. Arch Neurol. 1992;49(1):61–4.
  14. Barkovich AJ, Guerrini R, Battaglia G, Kalifa G, N'Guyen T, Parmeggiani A, et al. Band heterotopia: correlation of outcome with magnetic resonance imaging parameters. Ann Neurol. 1994;36(4):609–17.
  15. Guerrini R, Filippi T. Neuronal migration disorders, genetics, and epileptogenesis. J Child Neurol. 2005;20(4):287–99.
  16.  Shnayder NA, Dmitrenko DV, Govorina YB, Kantimirova EA, Alekseeva OV, Molgachev AA, Makarkin AA. The late diagnosis of double cortex syndrome in a 36-year-old woman with resistant atonic seizures. Neurology, Neuropsychiatry, Psychosomatics. 2015;7(3):40-45. doi: 10.14412/2074-2711-2015-3-40-45. [Article in Russian].
  17. Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pilz DT, Ledbetter DH, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology. 1999;53(2):270–7.
  18. Hehr U, Uyanik G, Aigner L, Couillard-Despres S, Winkler J. DCX-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2007 Oct 19 [updated 2011 Mar 24].
  19. Aigner L, Uyanik G, Couillard-Despres S, Ploetz S, Wolff G, Morris-Rosendahl D, et al. Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders. Neurology. 2003;60(2):329–32.
  20. Demelas L, Serra G, Conti M, Achene A, Mastropaolo C, Matsumoto N, et al. Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology. 2001;57(2):327–30.
  21. Moreira I, Bastos-Ferreira R, Silva J, Ribeiro C, Alonso I, Chaves J. Paternal transmission of subcortical band heterotopia through DCX somatic mosaicism. Seizure. 2015;25:62-4. doi: 10.1016/j.seizure.2014.12.005.
  22. Zhagn K, Li S, Wen H, Yuan Y. Prenatal diagnosis of fetal gray matter heteropia in one case and literature review. Nan Fang Yi Ke Da Xue Xue Bao. 2015;35(12):1770-4. [Article in Chinese].
  23. Levine D. Fetal magnetic resonance imaging. J Matern Fetal Neonatal Med. 2004;15(2):85-94.
  24. Bahi-Buisson N, Souville I, Fourniol FJ, Toussaint A, Moores CA, Houdusse A, et al; SBH-LIS European Consortium. New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum. Brain. 2013;136(Pt 1):223-44. doi: 10.1093/brain/aws323.
  25. Parisi P, Miano S, Mei D, Paolino MC, Castaldo R, Villa MP. Diffuse subcortical band heterotopia, periodic limb movements during sleep and a novel “de novo” mutation in the DCX gene. Brain Dev. 2010;32(6):511–5. doi: 10.1016/j.braindev.2009.06.007.
  26. Dericioglu N, Oguz KK, Ergun EL, Tezer FI, Saygi S. Ictal/interictal EEG patterns and functional neuroimaging findings in subcortical band heterotopia: Report of three cases and review of the literature. Clin EEG Neurosci. 2008;39(1):43–9.
  27. Kaur S, Ghuman MS, Devarajan LJ. A pediatric epilepsy classic: “Double cortex” syndrome. J Pediatr Neurosci. 2015;10(2):125-6. doi: 10.4103/1817-1745.159201.

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International Journal of Biomedicine. 2017;7(1):67-70. © 2017 International Medical Research and Development Corporation. All rights reserved