Phenotypic and molecular insights into CASK-related disorders in males

• DOI: 10.1186/s13023-015-0256-3
• Publication Date: 2015-04-11T07:08:31Z
• Authors: Ute Moog; Tatjana Bierhals; Kristina Brand; Jan Bautsch; Saskia Biskup; Thomas Brune; Jonas Denecke; Christine E de Di...; Christina Evers; Maja Hempel; Marco Henneke; Helger Yntema; Björn Menten; Joachim Pietz; Rolph Pfundt; Jörg Schmidtke; Doris Steinemann; Constance T Stumpel; Lionel Van Maldergem; Kerstin Kutsche
• Keywords: CASK; Sanger sequencing

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