Abstract
We report a 9-year-old Spanish boy with severe psychomotor developmental delay, short stature, microcephaly and abnormalities of the brain morphology, including cerebellar atrophy. Whole-exome sequencing (WES) uncovered two novel de novo variants, a hemizygous variant in CASK (Calcium/Calmodulin Dependent Serine Protein Kinase) and a heterozygous variant in EEF2 (Eukaryotic Translation Elongation Factor 2). CASK gene encodes the peripheral plasma membrane protein CASK that is a scaffold protein located at the synapses in the brain. The c.2506‐6 A > G CASK variant induced two alternative splicing events that account for the 80% of the total transcripts, which are likely to be degraded by NMD. Pathogenic variants in CASK have been associated with severe neurological disorders such as mental retardation with or without nystagmus also called FG syndrome 4 (FGS4), and intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH). Heterozygous variants in EEF2, which encodes the elongation factor 2 (eEF2), have been associated to Spinocerebellar ataxia 26 (SCA26) and more recently to a childhood-onset neurodevelopmental disorder with benign external hydrocephalus. The yeast model system used to investigate the functional consequences of the c.34 A > G EEF2 variant supported its pathogenicity by demonstrating it affects translational fidelity. In conclusion, the phenotype associated with the CASK variant is more severe and masks the milder phenotype of EEF2 variant.
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Data availability
The data of the study (variant and phenotype) have been submitted to LOVD database (patient ID 00411450).
Change history
26 May 2023
A Correction to this paper has been published: https://doi.org/10.1038/s10038-023-01164-y
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Acknowledgements
We thank the patient and his family for their contribution.
Funding
This project was supported by the Spanish Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (ERDF) (grant PI17/00487 and PI20/00150 to FM-A). FJC-V and MER-G were supported by ISCIII-ERDF (PI17/00487 and PI20/00150).
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MER-G, FJC-V and MTS-C performed the experimental work on CASK; JDD, BBAdV and MJNS performed and evaluated functional assays on EEF2; AMA, RSdlH and PQ-F examined the patients and characterized the clinical features of the disease; FM-A supervised the study, interpreted data and wrote the original draft of the manuscript. All authors reviewed the final manuscript.
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The Ethic Committee of the Instituto de Investigación Hospital 12 de Octubre (i + 12) approved the study, and written informed consent was obtained from the patient’s parents.
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The original online version of this article was revised: Dr. Alexandra N. Olson was missing.
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Rodríguez-García, M.E., Cotrina-Vinagre, F.J., Olson, A.N. et al. A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2. J Hum Genet 68, 543–550 (2023). https://doi.org/10.1038/s10038-023-01150-4
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DOI: https://doi.org/10.1038/s10038-023-01150-4