Comprehensive investigation of CASK and other relevant genes in 41 patients with intellectual disability, microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH) using next-generation sequencing. S. Hayashi1, N. Okamoto2, J. Takanashi3, J. Inazawa1 1) Dept Molec Cytogenetics, Tokyo Med & Dental Univ, Tokyo, Japan; 2) Dept. 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 central nervous system of both adults and fetuses and plays 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] mostly 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 41 patients presenting with typical MICPCH in order to investigate CASK aberrations. So far, we have detected various types of CASK aberrations in 27 of 41 patients (65.9%): large deletions in 6 patients, intragenic duplication or complex rearrangement in 3 patients, point mutations in 18 patients and other aberrations in 3 patients. Subsequently, we have investigated the CASK-negative cases using next-generation sequencing. We screened the remaining 14 cases by target-resequencing of all exons of 17 selected genes responsible for microcephaly and/or pontocerebellar hypoplasia, along with the entire region of CASK including all exons, introns and promoter region, and we identified novel candidate mutations in two cases. Also, we screened a trio of a patient and their parents by whole exome sequencing. Our research comprehensively clarified a correlation between these genotypes and phenotypes of MICPCH, and suggested that not only CASK but also other several genes are involved in the etiology of MICPCH.

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