Research Explained: Expanding the Phenotypic Spectrum of CSNK2A1-associated Okur-Chung Neurodevelopmental Syndrome (2024 Pre-print)

Authors: Swetha Ramadesikan, Iftekhar A. Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A. Varga, Umamaheswaran Gurusamy, Matthew T. Pastore, Emily R. Sites,

Murugu Manickam, Dennis W. Bartholomew, Jesse M. Hunter, Peter White, Richard K. Wilson, Rolf W. Stottmann, Daniel C. Koboldt

Research Explained By: Tierney Baum, PhD, Strategic R&D Consultant

Link to Publication: https://linkinghub.elsevier.com/retrieve/pii/S2666-2477(24)00119-2

Research Explained Summary:

Microcephaly, or smaller head size, has been reported in patients with OCNDS, but at the time of writing this publication microcephaly was not currently listed in the overall clinical spectrum of symptoms for OCNDS in the Online Mendelian Inheritance in Man database (OMIM). OMIM is a comprehensive collection of human genes and their associated genetic phenotypes (traits). Researchers in this study describe four individuals with OCNDS as well as an analysis of symptoms that are present in patients presented in existing OCNDS publications. They found that individuals with OCNDS, on average, have a smaller head circumference. The study also concluded that ~1/3rd of OCNDS individuals have full microcephaly.

Strikingly, study investigators also found that microcephaly was associated with specific patient variants in the CSNK2A1 gene that affect different parts of the protein made by CSNK2A1, called CK2. 36% of individuals with variants in the kinase domain of CK2 (amino acids 39-324 representing approximately 75% of the protein) presented with microcephaly compared to only 14% of individuals with variants in other domains of the protein.

The kinase domain of the CK2 protein is essential for activating the protein; dysfunction of this domain often results in fewer functioning CK2 proteins in the cell. Furthermore, a section of the kinase domain, called the ATP/GTP loop (also known as the Gly-rich loop), is critical for this activation because it is where the molecule that stores and releases energy for cells binds. Researchers found that up to 62% of patients with variants in this segment of CK2 (amino acids 49-53) had microcephaly.

The two main conclusions of this paper were:

1. Microcephaly is relatively common in OCNDS patients and should be included in the clinical list of symptoms.
2. Microcephaly significantly correlates with the location of the CSNK2A1 variant.

Researchers suggest further studies are needed to investigate if there are other connections between patient symptom profiles and their specific variant. This study is a step forward in understanding how patient variants may affect symptom presentation in children with OCNDS.