Alternative titles; symbols
HGNC Approved Gene Symbol: CASK
Cytogenetic location: Xp11.4 Genomic coordinates (GRCh38) : X:41,514,934-41,923,554 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.4 | FG syndrome 4 | 300422 | X-linked recessive | 3 |
| Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia | 300749 | X-linked | 3 | |
| Intellectual developmental disorder, with or without nystagmus | 300422 | X-linked recessive | 3 |
The CASK gene encodes a calcium/calmodulin-dependent serine protein kinase that is a member of the membrane-associated guanylate kinase (MAGUK) protein family. MAGUKs are scaffolding proteins associated with intercellular junctions (summary by Atasoy et al., 2007).
Cohen et al. (1998) used degenerate PCR to clone human CASK cDNAs from several libraries. CASK encodes a 921-amino acid polypeptide with an N-terminal calcium/calmodulin-dependent protein kinase-like domain, PDZ and SH3 domains, a potential protein 4.1-binding motif, and a domain homologous to guanylate kinase. Human CASK is 99% and 52% identical to rat CASK and C. elegans LIN2, respectively. Northern blot analysis demonstrated that CASK is ubiquitously expressed. Immunofluorescence localized the CASK protein to lateral and/or basal plasma membrane domains in epithelial cells.
Dimitratos et al. (1998) used radiation hybrid panels to map the CASK gene to human chromosome Xp11.4. Stevenson et al. (2000) confirmed the assignment of the CASK gene to Xp11.4 by inclusion within a YAC contig.
Cohen et al. (1998) determined that CASK interacts with both syndecan-2 (SDC2; 142460) and the actin-binding band 4.1 protein (130500). They suggested that CASK may function as a cytoskeletal membrane scaffold that coordinates signal transduction pathways within the cortical cytoskeleton.
Butz et al. (1998) identified a complex of 3 proteins in brain that has the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. The 3 proteins are CASK; Mint1 (APBA1; 602414), a putative vesicular trafficking protein; and Veli1 (603380), -2, and -3, vertebrate homologs of C. elegans LIN7. CASK, Mint1, and the Velis form a tight, salt-resistant complex. All of these proteins contain PDZ domains in addition to other modules. Butz et al. (1998) proposed that the tripartite complex acts as a nucleation site for the assembly of proteins involved in synaptic vesicle exocytosis and synaptic junctions.
Using immunoprecipitation experiments, Tabuchi et al. (2002) determined that Caskin1 (612184), like Mint1, is stably bound to CASK in the brain. Affinity chromatography experiments determined that Caskin1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin-1 (600565), suggesting that CASK and Caskin1 coat the cytoplasmic tails of neurexins and other cell surface proteins. Detailed mapping studies revealed that Caskin1 and Mint1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. GST-pull-down experiments indicated that CASK forms a tripartite complex with Caskin1 and Velis similar to the CASK-Mint1-Veli complex.
To identify binding partners for the guanylate kinase domain of CASK, Hsueh et al. (2000) carried out a yeast 2-hybrid screen of brain complementary DNA libraries, from which TBR1 (604616) was isolated. By deletion analysis, the C-terminal region of TBR1 (residues 342 to 681) was found to be necessary and sufficient for association with the guanylate kinase domain of CASK. When coexpressed in COS-7 cells, TBR1 and CASK were readily coprecipitated by antibodies directed against either individual protein. Hsueh et al. (2000) demonstrated that CASK enters the nucleus and binds to a specific DNA sequence (the T element) in a complex with TBR1. CASK acts as a coactivator of TBR1 to induce transcription of T element-containing genes, including reelin, a gene that is essential for cerebrocortical development. On the basis of their findings, Hsueh et al. (2000) concluded that a membrane-associated guanylate kinase, which is usually associated with cell junctions, has a transcription regulation function.
Experiments with vesicles containing NMDA receptor 2B (NR2B subunit; 138252) showed that they are transported along microtubules by KIF17 (605037), a neuron-specific molecular motor in neuronal dendrites. Setou et al. (2000) demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10 (602414), which is a constituent of a large protein complex including Lin2 (CASK), Lin7 (603380), and the NR2B subunit. Setou et al. (2000) concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis.
Lu et al. (2003) showed that Cmg, the Drosophila homolog of CASK, associated with Camk2 (CAMK2A; 114078) in an ATP-regulated manner. In the presence of Ca(2+)/calmodulin (CALM1; 114180), Camk2 complexed to Cmg autophosphorylated at thr287 and became constitutively active. In the absence of Ca(2+)/calmodulin, Camk2 inactivated itself by autophosphorylation on thr306 and required a phosphatase to become reactivated. Lu et al. (2003) concluded that interaction between Cmg and Camk2 provides a postsynaptic pool of Camk2 that can be controlled locally to differentiate active and inactive synapses.
Hsueh (2009) reviewed the synaptic functions of the CASK protein, noting that it has 3 main roles: it regulates presynaptic termini formation and interactions at the presynaptic site; maintains the morphology of dendritic spines at the postsynaptic site; and regulates ion channels at the postsynaptic site. These functions of CASK can explain, at least in part, the mental retardation and brain developmental defects in patients with CASK mutations.
Intellectual Developmental Disorder with Microcephaly and Pontine and Cerebellar Hypoplasia
Najm et al. (2008) found heterozygous loss-of-function mutations in CASK in 4 girls and a partly penetrant splice mutation in a severely affected boy with a syndrome of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; 300749).
In 20 girls with MICPCH, Moog et al. (2011) identified different loss-of-function mutations or deletions/duplications in the CASK gene (see, e.g., 300172.0010-300172.0012). High-resolution molecular karyotyping of 8 girls found that 6 had intragenic deletions and 2 had intragenic duplications. The smallest deletion was a de novo 60-kb deletion; 1 patient had a 4.24-Mb deletion encompassing the entire gene. Sequence analysis in 12 patients identified 10 heterozygous mutations in 9 patients. The remaining 3 patients were found to have deletions involving CASK using FISH or RT-PCR. All mutations in patients with parental information were shown to occur de novo. All mutations were predicted or demonstrated to result in a null allele. The 20 patients, as well as 5 previously reported patients, had a remarkably similar phenotype, including moderate to severe psychomotor development with poor growth, hypotonia, lack of speech, and lack of ambulation. There was also a distinctive dysmorphic phenotype, with severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. Brain MRI showed varying degrees of proportionate pontocerebellar hypoplasia, normal corpus callosum, and simplified gyration pattern in some. Moog et al. (2011) emphasized that the brain malformation phenotype in females caused by loss-of-function mutations in CASK is different from the milder phenotype caused by hypomorphic mutations in CASK in males, which results in variable intellectual disability with or without nystagmus (FGS4; 300422).
By targeted analysis of the CASK gene in 10 unrelated Japanese girls with clinical features suggestive of MICPCH, Hayashi et al. (2012) found genomic aberrations of the CASK gene resulting in a null mutation in all. Three had nonsense mutations, 1 had a 1-bp deletion, 2 had splice site mutations, 2 had heterozygous deletions encompassing the CASK gene, and 2 had intragenic duplications affecting the CASK gene. All patients for whom parental DNA was available were found to carry de novo mutations. There were no molecular hotspots, and the phenotypes were similar regardless of the mutation. The findings extended the variety of genetic alterations causing CASK null mutations, including copy number variations.
In 8 male patients (7 with MICPCH with or without severe epilepsy and 1 (patient 8) with microcephaly with developmental delay), Moog et al. (2015) identified CASK alterations by Sanger sequencing, copy number analysis (MLPA and/or FISH), and array CGH. Sequence analysis revealed 3 pathogenic mutations: a nonsense mutation (R27X; 300172.0016) in patient 4, a 5-bp deletion (300172.0017) in patient 1, and a transition affecting the start codon (300172.0018) in patient 3. All of these patients exhibited MICPCH with the severe epileptic encephalopathy phenotype. In the 2 patients with MICPCH without epilepsy, MLPA identified mosaic deletions of the CASK gene, including a mosaic deletion of exon 1 (300172.0019) in patient 6. Moog et al. (2015) proposed that CASK mutation-positive males could be distinguished into 3 phenotypic groups that represent a clinical continuum, with inactivating CASK germline mutations associated with the most severe phenotype (MICPCH with severe epileptic encephalopathy); CASK mutations in the mosaic state or partly penetrant CASK mutations associated with the attenuated phenotype (MICPCH); and CASK missense and splice site mutations that leave the CASK protein intact but likely alter function or reduce the amount of normal protein, associated with intellectual disability with or without nystagmus (see 300422).
In a 9-year-old girl with MICPCH, LaConte et al. (2019) identified a heterozygous missense mutation in the CASK gene (L209P; 602414.0013). Overexpression of the L209P mutation in HEK293 cells resulted in abnormal cytoplasmic aggregates. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see NRXN1, 600565) and VELI (see LIN7A, 603380) but disrupted interaction with MINT1 (APBA1; 602414). Accordingly, MINT1 interacts with CASK's CaMK binding domain, where the mutation is located. LaConte et al. (2019) concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. Clinical features in the patient included microcephaly, cerebellar hypoplasia, and bilateral retinal dystrophy. It had initially been reported that mutations in the C terminus of CASK were responsible for nystagmus, but this patient also had nystagmus and the L209P mutation is in the N terminus.
FG Syndrome 4
In affected members of an Italian family with FG syndrome-4 (300422), Piluso et al. (2009) identified a missense mutation (300172.0003) in the CASK gene that segregated fully with the disease and was not found in 1,000 ethnically matched control X chromosomes.
In a boy with FG syndrome-4 and nystagmus, Dunn et al. (2017) identified a homozygous splice mutation in the CASK gene (300172.0014). Sanger sequencing in the parents demonstrated that this mutation was de novo.
Impaired Intellectual Development with or without Nystagmus
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked impaired intellectual development (see 300422). They identified 4 families with missense mutations in the CASK gene. In 2 of the families, the X-linked mental retardation segregated with nystagmus.
In 2 additional families with X-linked impaired intellectual development and nystagmus, Hackett et al. (2010) identified 2 different mutations in the CASK gene (300172.0008 and 300172.0009, respectively). In conjunction with the report of Tarpey et al. (2009), CASK mutations were found in 1.5% of individuals with XLMR who were screened. Families with mutations in the C-terminal part of the gene had nystagmus, suggesting a possible genotype/phenotype correlation.
By next-generation sequencing in a 5-year-old boy with impaired intellectual development, autism spectrum disorder, and microcephaly, who did not have nystagmus, Seto et al. (2017) identified a missense mutation in the CASK gene (S475I; 300172.0015). The mutation was identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she shared autistic symptoms with her brother. The mother showed an almost completely skewed X-chromosome inactivation pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated.
Atasoy et al. (2007) found that Cask-null mice died within hours of birth and exhibited a partially penetrant cleft palate phenotype and increased apoptosis in the thalamus, but no other major developmental changes. Neurons cultured from Cask-null mice showed no changes in electrical properties or evoked release, formed structurally normal synapses, but did show increased glutamatergic spontaneous release events. The findings indicated that Cask is required for mouse survival without being required for core neuronal activities.
Using a Cre/lox expression system, Srivastava et al. (2016) generated mouse models with absence of Cask expression first in Purkinje cells and then in cerebellar granule cells. No specific motor or other deficits were identified in either mutant mouse model. Complete Cask knockout of neurons in mice did not result in neonatal lethality; however, the mutant mice developed seizures that were fatal before 23 to 24 days of life. Female mice with a heterozygous neuronal-specific CASK knockout did not have an observable abnormal phenotype, but, conversely, female mice with a full-body constitutive heterozygous knockout of Cask had microcephaly, decreased cerebellar size, optic nerve hypoplasia, and signs of ataxia. Examination of individual brain cells in the heterozygous mutant female mice demonstrated that CASK null cells were equally viable compared to CASK-positive cells. Thus the microcephaly in the mice was not due to a cell-autonomous loss of Cask null cells, but rather another postnatal non-cell autonomous mechanism. Srivastava et al. (2016) then identified reduced mitochondrial respiration in brain homogenates of the heterozygous mutant female mice and lower oxidation of fatty acid and glucose in the muscles, although how this related to the neuronal phenotype of CASK loss in the heterozygous mutant female mice was not determined.
In female heterozygote CASK knockout mice (Cask +/-), Guo et al. (2023) found that the overall size of cerebellum was reduced compared to wildtype due to the death of cerebellar granule (CG) cells. Analysis of homozygous Cask knockout CG cells showed that cell death was apoptotic and was independent of Bdnf (113505) secretion mediated by neurexins (600565). Rescue analysis in cultured CG cells showed that the CaMK, PDZ, and SH3 domains of Cask were required for the survival of CG cells. Accordingly, in human patients manifesting neurologic symptoms, the authors identified CASK missense mutations in the CaMK, PDZ, or SH3 domains that affected the survival of CG cells. Three of the mutations, R106P, R255C, and Y268H (300172.0004), were located in the CaMK domain and resided on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (603143), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain was involved in the molecular mechanism by which CASK maintained CG cell survival.
Tello et al. (2023) found a Cask loss-of-function mutation caused microcephaly, microencephaly, and a form of short stature in Drosophila. Cultured neurons from mutant Drosophila had disrupted neurite-arbor morphogenesis, leading to a bushy phenotype. The severity of the busy phenotype was inversely related to Cask gene dosage, and the phenotype improved by transgenic expression of Cask. The authors developed a microfluidic system for standardized, automated dissociation of Drosophila central nervous system tissue into individual viable neurons, and this microfluidic system reproduced the bushy phenotype of Cask mutant neurons with high fidelity. Moreover, this automated dissociation method was also effective for rodent CNS.
In a female with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; 300749), Najm et al. (2008) identified a C-to-T transition at nucleotide 1915 in exon 21 of the CASK gene, resulting in a premature termination codon replacing the arginine at codon 639 (R639X). This mutation was not identified in the parents of the individual or in 150 control X chromosomes.
In a boy with microcephaly and disproportionate pontine and cerebellar hypoplasia (300749), Najm et al. (2008) identified a G-to-A transition at nucleotide 915 of the CASK gene, resulting in a synonymous mutation (K305K) located in the last nucleotide of exon 9. In vitro splicing analyses using minigene constructs identified skipping of exon 9 in about 20% of mutant transcripts, suggesting a defect in splicing. The affected individual was male and died at 2 weeks of age, thus being more severely affected than females described by Najm et al. (2008).
In affected members of an Italian family with FG syndrome-4 (300422), Piluso et al. (2009) identified a hemizygous 83G-T transversion in exon 2 of the CASK gene, resulting in an arg28-to-leu (R28L) substitution at a highly conserved residue in the CaM-kinase domain. There were 3 affected males and 2 carrier females; 1 of the females had a milder phenotype, with mild mental retardation, hypertelorism, and long philtrum. The mutation segregated fully with disease in the family and was not found in 1,000 ethnically matched control X chromosomes. Functional, structural, and dynamic studies did not reveal significant alterations induced by the R28L substitution; however, the authors observed partial skipping of exon 2 of CASK, suggesting improper recognition of an exonic splicing enhancer (ESE) motif induced by the mutation. RT-PCR analysis confirmed that the exon 2-skipped transcript was differently expressed in affected males and carrier females and was not detectable in either unaffected family members or controls,
In a 3-generation pedigree segregating X-linked intellectual developmental disorder with nystagmus (see 300422), Tarpey et al. (2009) identified a C-to-T transition at nucleotide 829 of the CASK gene, resulting in a tyr-to-his substitution at codon 268 (Y268H). The mutation segregated with the phenotype in the family and was not identified in any unaffected male family members.
Variant Function
Guo et al. (2023) showed that the Y268H mutation in CASK affects the survival of cerebellar granule (CG) cells, is located in the CaMK domain, and resides on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (603143), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain is involved in the molecular mechanism by which CASK maintained CG cell survival.
In a large family segregating X-linked intellectual developmental disorder with nystagmus (see 300422), Tarpey et al. (2009) identified an A-to-G transition at nucleotide 2129 of the CASK gene, predicted to result in an asp-to-gly substitution at codon 710 (D710G). However, RT-PCR analysis showed that the 2129A-G change introduces a splice site affecting exon 22 that removes 27 bp of the coding sequence and thus 9 amino acids of the protein at the C-terminal end of the 'Hook Motif.' This mutation segregated with intellectual developmental disorder and nystagmus in affected family members. An additional family member who had mental retardation without nystagmus was not found to carry this mutation. This individual was considered to have milder mental retardation than other affected family members.
In a family (family 123) in which 3 sons had X-linked intellectual developmental disorder and nystagmus (see 300422), Tarpey et al. (2009) identified a c.2767C-T transition in the CASK gene, resulting in a trp914-to-arg substitution. The mutation segregated with the phenotype.
In an erratum of Hackett et al. (2010), the authors corrected the mutation in family 123, originally reported by Tarpey et al. (2009), to a c.2755T-C transition, resulting in a trp919-to-arg (W919R) substitution.
In a pedigree segregating X-linked intellectual developmental disorder without nystagmus (see 300422), Tarpey et al. (2009) identified a C-to-T transition at nucleotide 1186 in the CASK gene, resulting in a pro-to-ser substitution at codon 396 (P396S). The mutation was found in affected family members only. This mutation was not associated with nystagmus.
In 2 brothers with X-linked intellectual developmental disorder and nystagmus (see 300422), Hackett et al. (2010) identified a 2183A-G transition in exon 23 of the CASK gene, resulting in a tyr728-to-cys (Y728C) substitution in a highly conserved residue. A sister of the brothers, who was affected and also carried the mutation, showed skewed X inactivation. The proband, who had severely impaired intellectual development , also showed cerebellar hypoplasia and pachygyria. He had congenital nystagmus, strabismus, and mild optic disc pallor. He also had dysmorphic features, including synophrys, high nasal bridge, upslanting palpebral fissures, and short columella. His brother had similar features. The sister had normal brain MRI, mildly impaired intellectual development, congenital nystagmus, and no dysmorphic features.
In affected members of a family with X-linked intellectual developmental disorder and nystagmus (see 300422), Hackett et al. (2010) identified an A-to-T transversion affecting the 3-prime acceptor splice site of exon 26, resulting in the production of 2 aberrant transcripts: one lacking exon 26 and 1 lacking 3 amino acids.
See 300172.0014 for discussion of an A-to-G substitution at the same nucleotide.
In a 3.5-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a de novo heterozygous 316C-T transition in exon 4 of the CASK gene, resulting in an arg106-to-ter (R106X) substitution. The child had microcephaly (-6.3 SD), poor growth, severe developmental delay, hypotonia, sensorineural hearing loss, and myopia. She had never achieved walking. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. Dysmorphic facial features included flat occiput, almond-shaped eyes, beaked nose, broad and prominent nasal bridge and tip, smooth philtrum, and large ears.
In a 4-year-old Moroccan girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a de novo heterozygous 100-kb deletion affecting exon 1 of the CASK gene, predicted to result in a null allele. The child had microcephaly (-6 SD), severe developmental delay, hypotonia, dyskinesia, and pale optic disc; she could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. She had a broad nasal bridge, full lips, small chin, and large ears.
In an 8-year-old American girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a heterozygous 1639C-T transition in exon 17 of the CASK gene, resulting in a gln547-to-ter (Q547X) substitution. The patient had microcephaly (-5 SD), severe developmental delay, hypotonia, seizures, strabismus, and scoliosis. She could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia.
In a 9-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), LaConte et al. (2019) identified a heterozygous c.626T-C transition (c.626T-C, NM_003688.3) in the CASK gene, resulting in a leu209-to-pro (L209P) substitution in the CaMK protein domain. The mutation was identified by whole-exome sequencing and was shown to be de novo. Transient overexpression of mutant L209P CASK in HEK293 cells resulted in abnormal cytoplasmic aggregates and lower solubility compared to wildtype CASK protein. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see 600565) and VELI (see 603380) but disrupted interaction with MINT1 (602414). LaConte et al. (2019) concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1.
In a boy with nystagmus and FG syndrome-4 (FGS4; 300422), Dunn et al. (2017) identified a de novo hemizygous 3-prime acceptor splice site mutation in the CASK gene (IVS25-2A-G). The mutation was found by genome sequencing and confirmed by Sanger sequencing. Dunn et al. (2017) identified 3 different transcripts in the patient, including the wildtype transcript and 2 mutant transcripts. Mutant transcripts included the expected skipping of exon 26 as well as a 9-bp deletion associated with a cryptic splice site, leading to a 28-amino acid and a 3-amino acid in-frame deletion, respectively (Ala841_Lys843del and Ala841_Glu868del), in the C terminus. RNA-seq of the patient's RNA demonstrated exon skipping in 48% of the reads in the CASK gene and the use of a cryptic splice site in 52% of the reads. Wildtype RNA CASK was amplified only by RT-PCR and was not detected by RNA-seq. The predominant mutant transcripts contain an aberrant guanylate kinase domain and are thus predicted to degrade the ability of CASK to interact with important neuronal and ocular development proteins. Dunn et al. (2017) noted that patients reported by Hackett et al. (2010) with a pathogenic allele at the same position c.2521-2A-T (300172.0009) as their patient resulted in a different phenotype. The 4 patients reported by Hackett et al. (2010) presented with nystagmus, other ocular defects, and mild developmental/intellectual delay; 3 of them had childhood epilepsy or absence seizures and none had feeding issues. Dunn et al. (2017) proposed that different levels of expression of the 3 transcripts in their patient compared to the patients described by Hackett et al. (2010) might explain the difference in some of the phenotypic characteristics.
Seto et al. (2017) performed next-generation sequencing in a boy with intellectual developmental disorder without nystagmus (see 300422), who also had microcephaly and autism spectrum disorder, and identified a G-T transversion in exon 15 of the CASK gene, resulting in a ser475-to-ile (S475I) substitution. The variant was confirmed by Sanger sequencing and identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she did share autism spectrum disorder symptoms with her brother. Their mother showed an almost completely skewed X-inactivation (XCI) pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated.
In a male infant (patient 4) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo c.79C-T transition (c.79C-T, NM_003688) in exon 2 of the CASK gene, resulting in an arg27-to-ter (R27X) substitution. The patient was born at 34 weeks' gestation with intrauterine growth retardation and primary microcephaly (-2.57 SD). Medical history was significant for a ventricular septal defect, apnea-bradycardia syndrome, severe hypotonia, and seizures with onset at 2 months of life. MRI demonstrated severe pontocerebellar hypoplasia (especially the cerebellar hemispheres), progressive cerebral atrophy, and progressive hypomyelination.
In a male infant (patient 1) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo 5-bp deletion (c.704_708delATAAG, NM_003688) in exon 7 of the CASK gene, causing a frameshift predicted to result in a premature termination (Lys236GlufsTer10). RT-PCR on RNA isolated from patient fibroblasts revealed 5 different CASK transcript variants including a major transcript form that skipped exon 7. Immunoblot analysis did not detect CASK protein. The patient was born at 37 weeks' gestation with primary microcephaly and bilateral clubfeet. He had a severe neurologic disorder with hypotonia, abnormal movements, inability to swallow, and intractable seizures. MRI revealed severe hypoplasia of the medulla, pons, and cerebellum (especially the cerebellar hemispheres), progressive cortical atrophy, simplified gyri, and hypomyelination.
In a male infant (patient 3) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo c.1A-G transition (c.1A-G, NM_003688) in the CASK gene. The patient was born with a normal head circumference but head growth rapidly decelerated to -2.5 SD by age 3 months. He exhibited severe intractable seizures, severe hypotonia, feeding difficulties necessitating PEG tube, and optic hypoplasia, and demonstrated virtually no motor or cognitive development. MRI revealed significant hypoplasia of the pons and cerebellum. Saitsu et al. (2012) had previously described the same c.1A-G mutation in the start codon in a male patient (patient 2) with a diagnosis of Ohtahara syndrome.
In a male patient (patient 6) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2015) detected a mosaic deletion of exon 1. MLPA demonstrated that the relative peak area of the 2 probes for exon 1 was reduced by 50 to 60%, indicating a mosaic deletion. Somatic mosaicism of the exon 1 deletion was confirmed in buccal cell-derived DNA by MLPA as dosage of this exon was reduced by 60%. Moog et al. (2015) suggested that somatic mosaicism of the CASK gene produces wildtype protein in a significant percentage of the cells, most likely reducing clinical severity. Patient 6 showed progressive microcephaly during his first year of life and global developmental delay. He had a history of an afebrile seizure but otherwise had a normal EEG. MRI showed moderate pontocerebellar hypoplasia affecting the cerebellar hemispheres and vermis equally.
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