title: 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.
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: P
authors.initials: P
authors.lastname: Dunn
authors.affiliation: Department of Clinical Neuropsychology, Barrow Neurological Institute, Dignity Health St Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: G P
authors.initials: GP
authors.lastname: Prigatano
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: S
authors.initials: S
authors.lastname: Szelinger
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: A L
authors.initials: AL
authors.lastname: Siniard
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: A M
authors.initials: AM
authors.lastname: Claasen
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: R F
authors.initials: RF
authors.lastname: Richholt
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: M
authors.initials: M
authors.lastname: De Both
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: J J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: A M
authors.initials: AM
authors.lastname: Moskowitz
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: C
authors.initials: C
authors.lastname: Balak
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: I S
authors.initials: IS
authors.lastname: Piras
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: M
authors.initials: M
authors.lastname: Russell
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: A L
authors.initials: AL
authors.lastname: Courtright
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: N
authors.initials: N
authors.lastname: Belnap
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: S
authors.initials: S
authors.lastname: Rangasamy
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: K
authors.initials: K
authors.lastname: Ramsey
authors.affiliation: Department of Pediatrics/Medical Genetics, School of Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: J M
authors.initials: JM
authors.lastname: Opitz
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: D W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: V
authors.initials: V
authors.lastname: Narayanan
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: M J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: I
authors.initials: I
authors.lastname: Schrauwen
mesh_terms: D000293:Adolescent; D061085:Agenesis of Corpus Callosum / Q000175:diagnosis* / Q000235:genetics*; D001006:Anus, Imperforate / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003248:Constipation / Q000175:diagnosis* / Q000235:genetics*; D019066:Facies; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D051528:Guanylate Kinases / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D009123:Muscle Hypotonia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D009483:Neuropsychological Tests; D020417:Nystagmus, Congenital / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites
chemical_list: D022821:RNA Splice Sites; C106868:CASK kinases; D051528:Guanylate Kinases
keywords: CASK; FG syndrome; FGS4; X-linked intellectual disability; gastroesophageal; gastrointestinal; microcephaly; nystagmus