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

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 c...

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Published in:	American journal of medical genetics. Part A Vol. 173; no. 3; pp. 611 - 617
Main Authors:	Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., Russell, M., Courtright, A. L., Belnap, N., Rangasamy, S., Ramsey, K., Opitz, J. M., Craig, D. W., Narayanan, V., Huentelman, M. J., Schrauwen, I.
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-03-2017
Subjects:	Adolescent Agenesis of Corpus Callosum - diagnosis Agenesis of Corpus Callosum - genetics Anus, Imperforate - diagnosis Anus, Imperforate - genetics Atrophy CASK Cerebellum Child Child, Preschool Cognitive ability Constipation - diagnosis Constipation - genetics Facies Female FG syndrome FGS4 gastroesophageal gastrointestinal Gene deletion Gene Expression Genetic Association Studies Genotype & phenotype Genotypes Guanylate kinase Guanylate Kinases - genetics High-Throughput Nucleotide Sequencing Humans Hypoplasia In Situ Hybridization, Fluorescence Kinases Male Mental Retardation, X-Linked - diagnosis Mental Retardation, X-Linked - genetics Microcephaly Muscle Hypotonia - congenital Muscle Hypotonia - diagnosis Muscle Hypotonia - genetics Mutation Neuropsychological Tests Nystagmus Nystagmus, Congenital - diagnosis Nystagmus, Congenital - genetics Optic atrophy Phenotype Phenotypes Polymorphism, Single Nucleotide Ribonucleic acid RNA RNA Splice Sites Seizures Sensorimotor integration Short term memory X‐linked intellectual disability gastrointestinal microcephaly FGS4 gastroesophageal nystagmus CASK FG syndrome X-linked intellectual disability
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Summary:	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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1552-4825 1552-4833
DOI:	10.1002/ajmg.a.38069