A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2.

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.

• Authors: María Elena Rodríguez-García, Francisco Javier Cotrina-Vinagre, Alexandra N Olson, María Teresa Sánchez-Calvin, Ana Martínez de Aragón, Rogelio Simón de Las Heras, Jonathan D Dinman, Bert B A de Vries, Maria João Nabais Sá, Pilar Quijada-Fraile, Francisco Martínez-Azorín
• Journal: Journal of human genetics (J Hum Genet) Vol. 68 Issue 8 Pg. 543-550 (Aug 2023) ISSN: 1435-232X [Electronic] England
• PMID: 37072624 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.

Chemical References

• Peptide Elongation Factor 2

Topics

• Humans
• Microcephaly (genetics)
• Mutation
• Peptide Elongation Factor 2 (genetics)
• Phenotype
• Intellectual Disability (genetics)