Novel CASK mutations in cases with syndromic microcephaly

Francesca Cristofoli; Koen Devriendt; Erica Ellen Davis; Hilde Van Esch; Joris R. Vermeesch

doi:10.1002/humu.23536

Novel CASK mutations in cases with syndromic microcephaly

Francesca Cristofoli^*, Koen Devriendt, Erica Ellen Davis, Hilde Van Esch, Joris R. Vermeesch

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects, we established a transient loss-of-function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes. Furthermore, we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss-of-function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development.

Original language	English (US)
Pages (from-to)	993-1001
Number of pages	9
Journal	Human mutation
Volume	39
Issue number	7
DOIs	https://doi.org/10.1002/humu.23536
State	Published - Jul 2018

Funding

The authors wish to thank the patients and family members involved in this study. Furthermore, the authors thank the Aquatic Facility of KU Leuven for adult zebrafish maintenance and care. F.C. is PhD aspirant and H.V.E. is Clinical Investigator of the Research Foundation-Flanders (Fonds Wetenschappelijk Onderzoek, FWO, Belgium). The authors declare no conflict of interest. Genetic studies were approved by the Institutional Review Board of the University Hospitals of Leuven, and informed consent was obtained from the parents of each affected child for WES. The animal care and experimental procedures were carried out in accordance with the ethical committee guidelines for laboratory animal experimentation at KU Leuven. Contract grant sponsors: National Institute of Mental Health (R01 MH106826); KU Leu-ven (PFV/10/016 SymBioSys, GOA/12/015); Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program (IAP P7/43-BeMGI).

Keywords

CASK
cerebellar defects
loss-of-function
microcephaly
zebrafish

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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abstract = "Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects, we established a transient loss-of-function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes. Furthermore, we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss-of-function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development.",

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AU - Cristofoli, Francesca

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AU - Davis, Erica Ellen

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AU - Vermeesch, Joris R.

PY - 2018/7

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AB - Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects, we established a transient loss-of-function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes. Furthermore, we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss-of-function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development.

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Novel CASK mutations in cases with syndromic microcephaly

Abstract

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Keywords

ASJC Scopus subject areas

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