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Phenotypic spectrum associated with CASK loss-of-function mutations.
Moog, Ute 1; Kutsche, Kerstin 2; Kortum, Fanny 2; Chilian, Bettina 2; Bierhals, Tatjana 2; Apeshiotis, Neophytos 3; Balg, Stefanie 4; Chassaing, Nicolas 5; Coubes, Christine 6; Das, Soma 7; Engels, Hartmut 8; Van Esch, Hilde 9; Grasshoff, Ute 10; Heise, Marisol 2; Isidor, Bertrand 11; Jarvis, Joanna 12; Koehler, Udo 4; Martin, Thomas 13; Oehl-Jaschkowitz, Barbara 13; Ortibus, Els 14; Pilz, Daniela T 15; Prabhakar, Prab 16; Rappold, Gudrun 1; Rau, Isabella 2; Rettenberger, Gunther 17; Schluter, Gregor 18; Scott, Richard H 19; Shoukier, Moonef 20; Wohlleber, Eva 8; Zirn, Birgit 21; Dobyns, William B 22; Uyanik, Gokhan 2
[Article] Journal of Medical Genetics. 48(11):741-751, November 2011.

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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.