Phenotypic spectrum associated with CASK loss-of-function mutations. Issue 11 (27th September 2011)

• Record Type: Journal Article
• 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;
• Is Part Of: Journal of medical genetics. Volume 48:Issue 11(2011)
• Page Start: 741
• Page End: 751
• Publication Date: 2011-09-27
• Subjects: CASK -- microcephaly -- intellectual disability -- pontocerebellar hypoplasia -- X linked mental retardation -- other neurology -- molecular genetics -- chromosomal -- clinical genetics -- developmental, genetics -- visual development -- academic medicine -- diagnostics -- diagnostics tests -- copy-number -- epigenetics -- epilepsy and seizures -- genetic screening/counselling -- neurology -- neurosciences, neurology; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2011-100218
• Languages: English
• ISSNs: 1468-6244

Abstract

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.