Research Explained: Inherited CSNK2A1 variants in families with Okur-Chung neurodevelopmental syndrome (2023)

Authors: Newell Belnap, Aiai Price-Smith, Keri Ramsey, Kamawela Leka, Anna Abraham, Emma Lieberman, Katie Hassett, Sai Potu, Natasha Rudy, Kirstin Smith, Fady M. Mikhail, Kirstin G. Monaghan, Andrea Hendershot, Jeroen Mourmans, Maria Descartes, Matthew J. Huentelman, Jennifer Sills, Sampath Rangasamy, Vinodh Narayanan

Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern

Link to Paper: https://onlinelibrary.wiley.com/doi/10.1111/cge.14408

Research Explained Summary:

In this study, researchers profiled and compared OCNDS symptoms present within and across three families. This report is the first study of families with OCNDS inherited by children from their parents, instead of the more common inheritance pattern where the OCNDS genetic variant is new and only is present in the child. This report also confirms that both men and women with OCNDS are fertile.

When comparing each of these families, there was a striking difference in the symptoms experienced by each parent and child, even though the OCNDS genetic variant is the same. For example, two half-sisters (individuals that share only one parent) in a family with OCNDS experienced vastly different effects with one displaying behavioral issues, musculoskeletal problems, growth irregularities, and difficulty feeding among other symptoms that were present but much less severe in their half-sister. When comparing across families, symptoms were even more divergent, despite two families having the same disease-causing DNA variant. Although both families displayed the p.Lys198Arg (K198R) variant in the CSNK2A1 gene, the most common disease-causing variant found in OCNDS patients, one of the families had multiple cases of generalized muscle weakness (hypotonia), while the other instead experienced behavioral issues.

Together, this report shows that OCNDS symptoms vary greatly even within individuals with the same genetic changes causing OCNDS. These symptoms also varied within families, indicating that it is unlikely that researchers will be able to correlate specific OCNDS-causing DNA variants with specific symptoms. More generally, these findings indicate that there may be many people with undiagnosed OCNDS throughout the world due to the varying severity of symptoms and therefore varying diagnosis/treatment needs.