title: Phenotypic spectrum associated with CASK loss-of-function mutations.
abstract: 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.
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.forename: Fanny
authors.initials: F
authors.lastname: Kortüm
authors.forename: Bettina
authors.initials: B
authors.lastname: Chilian
authors.forename: Tatjana
authors.initials: T
authors.lastname: Bierhals
authors.forename: Neophytos
authors.initials: N
authors.lastname: Apeshiotis
authors.forename: Stefanie
authors.initials: S
authors.lastname: Balg
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.forename: Marisol
authors.initials: M
authors.lastname: Heise
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Joanna
authors.initials: J
authors.lastname: Jarvis
authors.forename: Udo
authors.initials: U
authors.lastname: Koehler
authors.forename: Thomas
authors.initials: T
authors.lastname: Martin
authors.forename: Barbara
authors.initials: B
authors.lastname: Oehl-Jaschkowitz
authors.forename: Els
authors.initials: E
authors.lastname: Ortibus
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Pilz
authors.forename: Prab
authors.initials: P
authors.lastname: Prabhakar
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.forename: Isabella
authors.initials: I
authors.lastname: Rau
authors.forename: Günther
authors.initials: G
authors.lastname: Rettenberger
authors.forename: Gregor
authors.initials: G
authors.lastname: Schlüter
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.forename: Moonef
authors.initials: M
authors.lastname: Shoukier
authors.forename: Eva
authors.initials: E
authors.lastname: Wohlleber
authors.forename: Birgit
authors.initials: B
authors.lastname: Zirn
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Gökhan
authors.initials: G
authors.lastname: Uyanik
mesh_terms: D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D051528:Guanylate Kinases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D007621:Karyotyping; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D059906:Neuroimaging; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D015415:Biomarkers; C106868:CASK kinases; D051528:Guanylate Kinases