Investigation of CASK gene aberrations in 38 patients with severe intellectual disability, microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH). S. Hayashi1, O. Nobuhiko2, J. Takanashi3, J. Inazawa1 1) Dept Molec Cytogenetics, Tokyo Med & Dental Univ, Tokyo, Japan; 2) Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan; 3) Department of Pediatrics, Kameda Medical Center, Chiba, Japan.

   The CASK gene [OMIM: *300172] at Xp11.4, encoding a member of the MAGUK (membrane-associated guanylate kinase) proteins, is highly expressed in the mammalian nervous system of both adults and fetuses, and it was reported to play several roles in neural development and synaptic function. While loss of function of CASK raised by mutation or genomic copy-number variant (CNV) causes intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [OMIM: #300749] in females, insufficiency of CASK probably leads to lethality in males. We reported a first case of MICPCH with heterozygous deletion at Xp11.4p11.3 including CASK in 2008, and thereafter we have recruited patients presenting with MICPCH in order to investigate CASK aberrations. So far, we have detected various types of CASK aberrations in 24 of 38 patients with MICPCH: large deletions in 6 patients, intragenic duplication or complex rearrangement in 3 patients and point mutations in 15 patients. Through this screening, we were able to detect other factors probably responsible for MICPCH, for example, a mosaic mutation of CASK in a male MICPCH patient, another type of genomic aberration involving in CASK or a deletion of another candidate gene. These results seem to suggest a novel etiology for MICPCH, thus we are currently examining a correlation between these genotypes and phenotypes. Moreover, we are also screening other candidate genes for CASK-negative MICPCH patients by target re-sequencing to detect another locus of MICPCH. Our research demonstrates a comprehensive etiology of MICPCH.

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