Research Explained: A Case of Okur-Chung Neurodevelopmental Syndrome with a Novel, de novo Variant on the CSNK2A1 Gene in a Turkish Patient

Authors: Drenushe Zhuri, Fulya Dusenkalkan, Guzin Tunca Alparslan, Hakan Gurkan

Written By: Tierney Baum, PhD, Strategic R&D Consultant

Link to publication: https://pmc.ncbi.nlm.nih.gov/articles/PMC10862324/

Most OCNDS patients are reported to have either a missense or nonsense variant in their CSNK2A1 gene.

In 2023 a research group from Trakya University reported a patient with a novel CSNK2A1 mutation. At the time of publication this was the first reported frameshift variant reported in an OCNDS patient.

Missense variant – a single change in the DNA sequence that results in a different amino acid substitution; often changes the function of the resulting protein  

Nonsense variant – a single change in the DNA sequence that results in a stop signal in the DNA resulting in a shorter and likely non-functioning protein

Frameshift variant – an addition or deletion of a nucleotide base in the DNA sequence which changes the amino acid ‘reading frame’; results in a chemically different protein with completely different amino acids following the change in sequence

Heterozygous - having one normal (unmutated) copy of a gene and one mutated copy

De novo - a change in DNA that happens for the first time in an individual and is not inherited from either parent. These mutations occur randomly in the sperm, egg, or early during embryo development and can sometimes lead to genetic conditions or traits that were not present in the family before.

At the time of publication, the reported patient was a 2-year-old male brought into the clinic with hypotonia. A physical exam showed observations of a wide forehead, flattened and wide upper nose, epicanthal folds in the right eye, low set ears, smaller jaw, and widened toes. Cranial MRI showed an underdeveloped myelination pattern and mild atrophy in two of the lateral ventricles resulting in being enlarged due to tissue loss.

Whole-exome DNA sequencing was performed, and the patient was found to have a heterozygous variant M381G (c.1139_1140GGdup; p.Met381GlyfsTer32) at the terminal end of the CSNK2A1 gene. This variant was novel and reported to lead to a frameshift mutation. Both parents were not found to have the mutation, so this variant was considered de novo in the child.

A protein analysis was done to better understand the possible functional changes of the reported variant protein. It was expected that this change would result in a longer form of the CK2 protein that may not be functional. The location of the variant likely has effects on many parts of the protein, so it was hypothesized that this mutation could affect how this protein binds to other subunits of CK2.

Researchers emphasize that more studies are needed to fully understand the effect of the variant. This study shows that the position and type of the CSNK2A1 variant are likely important factors for severity of patient symptoms and how they are present in the clinic.