Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)

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.

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

“…Due to this function, mutation of highly conserved residues in this inner helix is likely to alter the structure of the Ca 2+ channel and impact Ca 2+ release. For example, the microcephaly with pontine and cerebellar hypoplasia (MICPCH; MIM #300749)-associated T2552P introduces a more hydrophobic residue at this position which may disrupt the α-helical structure of this domain (Hayashi et al, 2017). PCH and MICPCH also exhibit similar symptoms to SCA29 including early-onset motor and cognitive impairments (Namavar et al, 2011b, Hayashi et al, 2017, Moog et al, 2011).…”

“…For example, the microcephaly with pontine and cerebellar hypoplasia (MICPCH; MIM #300749)-associated T2552P introduces a more hydrophobic residue at this position which may disrupt the α-helical structure of this domain (Hayashi et al, 2017). PCH and MICPCH also exhibit similar symptoms to SCA29 including early-onset motor and cognitive impairments (Namavar et al, 2011b, Hayashi et al, 2017, Moog et al, 2011). While patients may exhibit clinical variability, such as the presence of microcephaly, the characteristic neuroradiological finding in PCH and MICPCH patients is severe hypoplasia of both the cerebellum and the pons (Namavar et al, 2011a).…”

MPP1/p55 gene deletion in a hemophilia A patient with ectrodactyly and severe developmental defects

“…13 Similarly, the loss of discs-large gene in mice leads to craniofacial defects, abnormal eye morphology, cleft palate, and perinatal lethality. For example, loss of CASK in humans and mice causes significant defects including microcephaly, facial deformities, and intellectual disabilities.…”

“…For example, loss of CASK in humans and mice causes significant defects including microcephaly, facial deformities, and intellectual disabilities. 13 Similarly, the loss of discs-large gene in mice leads to craniofacial defects, abnormal eye morphology, cleft palate, and perinatal lethality. 14 Considering these findings, MPP1 may emerge as an important target for establishing normal morphological development in mammals.…”

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

“…Genetic variants in CASK were first described in cases with microcephaly with pontine and cerebellar hypoplasia (MICPCH), followed by the identification in cases with Xlinked ID (XL-ID), developmental delay (DD) and ASD (Deciphering Developmental Disorders, 2017;Iossifov et al, 2014;Moog et al, 2015;Moog et al, 2011). The majority of cases reported with CASK-related disorders are females with MICPCH, caused by heterozygous loss-of-function (LoF) variants (Burglen et al, 2012;Hayashi et al, 2017;Moog et al, 2011;Najm et al, 2008). Skewed X-chromosome inactivation (XCI) has shown protective effects against more severe phenotypes (Moog et al, 2011;Seto et al, 2017).…”