A de novo splice site mutation in CASK causes FG syndrome‐4 and congenital nystagmus

Abstract

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc.

A novel <i>CASK</i> mutation identified in siblings exhibiting developmental disorders with/without microcephaly

“…The proteins included in MAGUK family are scaffold proteins and are located at synapses in the brain. Various neurological disorders have been associated with CASK; FG syndrome (5,6), X-linked ID with/without nystagmus (7), and epileptic encephalopathy (8)(9)(10). In this study, a novel CASK mutation, c.1424G>T (p.Ser475Ile), was identified in siblings exhibiting DD with ID and/or ASD.…”

NovelCASKmutations in cases with syndromic microcephaly

“…The affected female from our cohort did not present such a severe phenotype. Considering her young age though, her clinical course might deteriorate, although a wide variability in clinical phenotype has been observed even among cases with variants predicted to have similar effects on protein functionality (Dunn et al, 2017).…”

“…In our cohort, three girls showed ophthalmologic anomalies and two of them specifically displayed nystagmus. Previous reports have indicated that congenital nystagmus is strongly associated with mutations localized in the GUK domain of CASK (Dunn et al, 2017; Hackett et al, 2010; Watkins et al, 2013). This domain interacts with FRMD7, a plasma membrane-cytoskeleton coupling protein, mutations of which cause X-linked congenital nystagmus (Tarpey et al, 2006).…”

Nystagmus

“…In children, vertical nystagmus may be linked to retinal dystrophies [62]. Different nystagmus patterns may be seen in newborn and infants with Joubert syndrome [63], mutations in the calcium/ calmodulin-dependent serine protein kinase (CASK) gene leading to FG-syndrome 4 [64], visual deprivation from child neglect [65], mass lesions above the midbrain [66] and galactokinase deficiency [67]. The differential diagnosis of isolated nystagmus in pediatric patients remains challenging.…”