Phenotypic and molecular insights into CASK-related disorders in males

Abstract

BackgroundHeterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date.MethodsWe identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data.ResultsCASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein.ConclusionsBased on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0256-3) contains supplementary material, which is available to authorized users.

Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

“…4 In some patients, typical progressive microcephaly with pontine and cerebral hypoplasia (MICPCH) develops. 4,10 In others, mild to severe mental retardation with or without nystagmus has been reported. 10 In some cases, autism-spectrum disorders (ASD) develop in patients with CASK mutations.…”

“…4,10 In others, mild to severe mental retardation with or without nystagmus has been reported. 10 In some cases, autism-spectrum disorders (ASD) develop in patients with CASK mutations. 10 These human genetic studies indicate that CASK is a critical gene for brain development and function.…”

“…[4][5][6][7][8][9] CASK mutations identified from patients are widely distributed across the entire gene, and no hot mutation spot in CASK linked to the disorder has been identified. 7,10 The phenotypes of patients with CASK mutations also vary. 10 It has been reported that CASK mutation may cause neonatal death in boys.…”

“…7,10 The phenotypes of patients with CASK mutations also vary. 10 It has been reported that CASK mutation may cause neonatal death in boys. 4 In some patients, typical progressive microcephaly with pontine and cerebral hypoplasia (MICPCH) develops.…”

Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

“…Patients with large deletions are phenotypically indistinguishable from patients with limited deletions to the CASK gene. In a series of 8 cases in men with mutations in the CASK gene 8,14 , they propose that patients with a more severe phenotype present a type of compromise in the germinal line, finding mosaicisms in patients with attenuated phenotype 15 . Several studies report the association of epilepsy in patients with PCH, but only in one previously published 16 , we describe the presence of a West Syndrome, just as our patient, which was detected in the video-EEG, tracing hypsarrhythmia.…”