Abstract
The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
Highlights
The CASK gene (OMIM: Ã300172), which encodes a member of the MAGUK protein family, is highly expressed in the mammalian nervous system of both adults and fetuses, and plays several roles in neural development and synaptic functions [1, 2]
Besides 32 cases in which the molecular diagnosis could be attributed to CASK loss-of-function mutations, including a rare somatic mosaic mutation in a male patient, we identified a mutation in ITPR1, another gene in which mutations are causative for microcephaly with pontine and cerebellar hypoplasia (MICPCH)
All patients were examined and evaluated by clinical dysmorphologists in each hospital and were enrolled in this study if they met the criteria for both microcephaly and pontocerebellar hypoplasia in brain magnetic resonance imaging (MRI) (Fig 1)
Summary
The CASK gene (OMIM: Ã300172), which encodes a member of the MAGUK (membraneassociated guanylate kinase) protein family, is highly expressed in the mammalian nervous system of both adults and fetuses, and plays several roles in neural development and synaptic functions [1, 2]. Due to its location on the X chromosome, loss-of-function of CASK usually leads to the manifestation of MICPCH in females, whereas a complete loss of this gene is believed to be lethal in males. The vast majority of typical MICPCH by CASK aberrations are seen in female patients [4,5,6,7,8]. Besides 32 cases in which the molecular diagnosis could be attributed to CASK loss-of-function mutations, including a rare somatic mosaic mutation in a male patient, we identified a mutation in ITPR1, another gene in which mutations are causative for MICPCH.
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