Journal Article

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

Stevenson, Roger E, Raymond, F Lucy, Hackett, Anna, Tolmie, John, Tarpey, Patrick S, Gecz, Jozef, Yates, John RW, Stratton, Michael R, Schwartz, Charles E, Grigg, John, Rogers, Carolyn, Shaw, Marie, Corbett, Mark, Whibley, Annabel, Partington, Michael, Licata, Andrea, Cox, James, Turner, Gillian, Boyle, Jackie, Wilson, Meredith, Futreal, Andrew P, Abidi, Fatima E

2010

Overview

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.

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: Amino Acid Sequence / Base Sequence / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Case-Control Studies / Chromosomes, Human, X - genetics / Cohort Studies / Cytogenetics / DNA Mutational Analysis / Facies / Family / Female / Fundamental and applied biological sciences. Psychology / Gene Expression / General aspects. Genetic counseling / Genetic Diseases, X-Linked - complications / Genetic Diseases, X-Linked - genetics / Genetics of eukaryotes. Biological and molecular evolution / Guanylate Kinases - chemistry / Guanylate Kinases - genetics / Human Genetics / Humans / Male / Medical genetics / Medical sciences / Mental Retardation, X-Linked - complications / Mental Retardation, X-Linked - enzymology / Mental Retardation, X-Linked - genetics / Microcephaly - complications / Microcephaly - genetics / Middle Aged / Molecular and cellular biology / Molecular Sequence Data / Mutation - genetics / Nystagmus, Congenital - complications / Nystagmus, Congenital - enzymology / Nystagmus, Congenital - genetics / Oculomotor disorders / Ophthalmology / Pedigree / Phenotype / X Chromosome Inactivation - genetics