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Title: Phenotypic spectrum associated with CASK loss-of-function mutations
Authors: Moog, Ute ×
Kutsche, Kerstin
Kortüm, Fanny
Chilian, Bettina
Bierhals, Tatjana
Apeshiotis, Neophytos
Balg, Stefanie
Chassaing, Nicolas
Coubes, Christine
Das, Soma
Engels, Hartmut
Van Esch, Hilde
Grasshoff, Ute
Heise, Marisol
Isidor, Bertrand
Jarvis, Joanna
Koehler, Udo
Martin, Thomas
Oehl-Jaschkowitz, Barbara
Ortibus, Els
Pilz, Daniela T
Prabhakar, Prab
Rappold, Gudrun
Rau, Isabella
Rettenberger, Günther
Schlüter, Gregor
Scott, Richard H
Shoukier, Moonef
Wohlleber, Eva
Zirn, Birgit
Dobyns, William B
Uyanik, Gökhan #
Issue Date: 2011
Publisher: BMJ Publishing Group
Series Title: Journal of Medical Genetics vol:48 issue:11 pages:741-751
Abstract: BackgroundHeterozygous 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.MethodsThe 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.Results11 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.ConclusionsThese 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.
URI: 
ISSN: 0022-2593
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Section Child - Miscellaneous (-)
× corresponding author
# (joint) last author

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