TY - JOUR
T1 - Phenotypic spectrum associated with CASK loss-of-function mutations
AU - Moog, Ute
AU - Kutsche, Kerstin
AU - Kortüm, Fanny
AU - Chilian, Bettina
AU - Bierhals, Tatjana
AU - Apeshiotis, Neophytos
AU - Balg, Stefanie
AU - Chassaing, Nicolas
AU - Coubes, Christine
AU - Das, Soma
AU - Engels, Hartmut
AU - Van Esch, Hilde
AU - Grasshoff, Ute
AU - Heise, Marisol
AU - Isidor, Bertrand
AU - Jarvis, Joanna
AU - Koehler, Udo
AU - Martin, Thomas
AU - Oehl-Jaschkowitz, Barbara
AU - Ortibus, Els
AU - Pilz, Daniela T.
AU - Prabhakar, Prab
AU - Rappold, Gudrun
AU - Rau, Isabella
AU - Rettenberger, Günther
AU - Schlüter, Gregor
AU - Scott, Richard H.
AU - Shoukier, Moonef
AU - Wohlleber, Eva
AU - Zirn, Birgit
AU - Dobyns, William B.
AU - Uyanik, Gökhan
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
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U2 - 10.1136/jmedgenet-2011-100218
DO - 10.1136/jmedgenet-2011-100218
M3 - Article
C2 - 21954287
AN - SCOPUS:81055126966
SN - 0022-2593
VL - 48
SP - 741
EP - 751
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 11
ER -