title: CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.
abstract: Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia. anna.hackett@hnehealth.nsw.gov.au
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.forename: Andrea
authors.initials: A
authors.lastname: Licata
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.forename: Annabel
authors.initials: A
authors.lastname: Whibley
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rogers
authors.forename: John
authors.initials: J
authors.lastname: Grigg
authors.forename: Michael
authors.initials: M
authors.lastname: Partington
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: John
authors.initials: J
authors.lastname: Tolmie
authors.forename: John Rw
authors.initials: JR
authors.lastname: Yates
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Futreal
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Fatima E
authors.initials: FE
authors.lastname: Abidi
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019066:Facies; D005190:Family; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000150:complications* / Q000235:genetics; D051528:Guanylate Kinases / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D008831:Microcephaly / Q000150:complications / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020417:Nystagmus, Congenital / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: C106868:CASK kinases; D051528:Guanylate Kinases