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Original article
Phenotypic spectrum associated with CASK loss-of-function mutations
  1. Ute Moog1,
  2. Kerstin Kutsche2,
  3. Fanny Kortüm2,
  4. Bettina Chilian2,
  5. Tatjana Bierhals2,
  6. Neophytos Apeshiotis3,
  7. Stefanie Balg4,
  8. Nicolas Chassaing5,
  9. Christine Coubes6,
  10. Soma Das7,
  11. Hartmut Engels8,
  12. Hilde Van Esch9,
  13. Ute Grasshoff10,
  14. Marisol Heise2,
  15. Bertrand Isidor11,
  16. Joanna Jarvis12,
  17. Udo Koehler4,
  18. Thomas Martin13,
  19. Barbara Oehl-Jaschkowitz13,
  20. Els Ortibus14,
  21. Daniela T Pilz15,
  22. Prab Prabhakar16,
  23. Gudrun Rappold1,
  24. Isabella Rau2,
  25. Günther Rettenberger17,
  26. Gregor Schlüter18,
  27. Richard H Scott19,
  28. Moonef Shoukier20,
  29. Eva Wohlleber8,
  30. Birgit Zirn21,
  31. William B Dobyns22,
  32. Gökhan Uyanik2
  1. 1Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
  2. 2Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  3. 3Privatpraxis für Humangenetik, Braunschweig, Germany
  4. 4Medizinisch Genetisches Zentrum, MGZ München, München, Germany
  5. 5Medical Genetics Department, Toulouse University Hospital and UPS III EA4555, Toulouse, France
  6. 6Genetic Services, A. de Villeneuve Hospital, Montpellier, France
  7. 7Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
  8. 8Institute of Human Genetics, University of Bonn, Bonn, Germany
  9. 9Centre for Human Genetics, University Hospitals Leuven, Leuven, Belgium
  10. 10Institute of Human Genetics, Department of Medical Genetics, Tübingen University, Tübingen, Germany
  11. 11Clinical Genetics Unit, University Hospital Nantes, Nantes, France
  12. 12Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK
  13. 13Gemeinschaftspraxis für Humangenetik, Homburg, Germany
  14. 14Department of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium
  15. 15Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
  16. 16Department of Neurology, Great Ormond Street Hospital for Children, London, UK
  17. 17Genetikum, Neu-Ulm, Germany
  18. 18Pränatalmedizin und Genetik Nürnberg/Bayreuth (MVZ), Nürnberg, Germany
  19. 19Department of Clinical Genetics, Great Ormond Street Hospital, London and Institute of Child Health, London, UK
  20. 20Institute of Human Genetics, University of Goettingen, Goettingen, Germany
  21. 21Department of Neuropediatrics, University of Goettingen, Goettingen, Germany
  22. 22Departments of Pediatrics and Neurology, and Center for Integrative Brain Research - Seattle Children's Research Institute, Seattle, Washington, USA
  1. Correspondence to Gökhan Uyanik, Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; g.uyanik{at}


Background Heterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia.

Methods The study characterised the CASK alteration in 20 new female patients by molecular karyotyping, fluorescence in situ hybridisation, sequencing, reverse transcriptase (RT) and/or quantitative real-time PCR. Clinical and brain imaging data of a total of 25 patients were reviewed.

Results 11 submicroscopic copy number alterations, including nine deletions of ∼11 kb to 4.5 Mb and two duplications, all covering (part of) CASK, four splice, four nonsense, and one 1 bp deletion are reported. These heterozygous CASK mutations most likely lead to a null allele. Brain imaging consistently showed diffuse brainstem and cerebellar hypoplasia with a dilated fourth ventricle, but of remarkably varying degrees. Analysis of 20 patients in this study, and five previously reported patients, revealed a core clinical phenotype comprising severe developmental delay/intellectual disability, severe postnatal microcephaly, often associated with growth retardation, (axial) hypotonia with or without hypertonia of extremities, optic nerve hypoplasia, and/or other eye abnormalities. A recognisable facial phenotype emerged, including prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and/or large ears.

Conclusions These findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.

  • CASK
  • microcephaly
  • intellectual disability
  • pontocerebellar hypoplasia
  • X linked mental retardation
  • other neurology
  • molecular genetics
  • chromosomal
  • clinical genetics
  • developmental, genetics
  • visual development
  • academic medicine
  • diagnostics
  • diagnostics tests
  • copy-number
  • epigenetics
  • epilepsy and seizures
  • genetic screening/counselling
  • neurology
  • neurosciences, neurology

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  • UM and KK contributed equally.

  • Funding This work was supported by grants from the Werner Otto-Stiftung (WOS 3/76 to GU) and the Deutsche Forschungsgemeinschaft (KU 1240/5-1 to KK). This work was part of the German Mental Retardation Network (MRNET) funded by the German Ministry of Research and Education as part of the National Genome Research Network NGFNplus (project reference numbers 01GS08162, 01GS08164, 01GS08168).

  • Competing interests None declared.

  • Patient consent Parental consent obtained.

  • Ethics approval The clinical data and samples were obtained with informed consent, including consent to use the photographs in this report, under protocols approved by Institutional Review Boards at all participating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.