Phenotypic spectrum associated with CASK loss-of-function mutations

Ute Moog, Kerstin Kutsche, Fanny Kortüm, Bettina Chilian, Tatjana Bierhals, Neophytos Apeshiotis, Stefanie Balg, Nicolas Chassaing, Christine Coubes, Soma Das, Hartmut Engels, Hilde Van Esch, Ute Grasshoff, Marisol Heise, Bertrand Isidor, Joanna Jarvis, Udo Koehler, Thomas Martin, Barbara Oehl-Jaschkowitz, Els OrtibusDaniela T. Pilz, Prab Prabhakar, Gudrun Rappold, Isabella Rau, Günther Rettenberger, Gregor Schlüter, Richard H. Scott, Moonef Shoukier, Eva Wohlleber, Birgit Zirn, William B. Dobyns, Gökhan Uyanik

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)741-751
Number of pages11
JournalJournal of medical genetics
Issue number11
StatePublished - Nov 2011
Externally publishedYes


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