Research Explained: De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features

Authors: Volkan Okur, Megan Cho, Lindsay Henderson, Kyle Retterer, Michael Schneider, Shannon Sattler, Dmitriy Niyazov, Meron Azage, Sharon Smith, Jonathan Picker, Sharyn Lincoln, Mark Tarnopolsky, Lauren Brady, Hans Bjornsson, Carolyn Applegate, Amy Dameron, Rebecca Willaert, Berivan Baskin, Jane Juusola, and Wendy Chung.

Publication Date: March 23, 2016

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

Link to article: https://link.springer.com/article/10.1007/s00439-016-1661-y

Research Explained Summary:

This study was the first to identify OCNDS as a distinct neurodevelopmental disorder (NDD) with causative mutations in the CSNK2A1 gene, setting it apart from other NDDs. Genetic sequencing of 4,102 pediatric patients with intellectual disability and/or developmental delay had already been performed, and within those patients, five were identified as having mutations in the CSNK2A1 gene with a unifying set of symptoms that have now come to define OCNDS. Mutations were found throughout the CSNK2A1 gene, with a different mutation in each individual reported. The mutations were defined as likely loss-of-function mutations, meaning that the mutation prevented normal function of this gene. The mutations were also heterozygous, meaning that among the two copies every individual has of each gene, only one copy was altered.

All patients identified in this study were female, although later studies would come to find male patients with OCNDS. All patients had developmental delay, while 4/5 showed a variety of symptoms including intellectual disability, behavioral issues, muscle weakness (hypotonia), speech issues, gastrointestinal issues, and dysmorphic facial features. 3/5 patients displayed decreased brain/head size (microcephaly), as well as musculoskeletal and immune issues. All these symptoms and their severity were highly variable between patients, but together formed a constellation of symptoms specific to OCNDS.

The CSNK2A1 gene encodes part of a protein known as CK2, which is involved in a variety of important biological processes including embryonic development and cell growth/survival. Specifically, it was already known that mice lacking both copies of this gene (which is not seen in humans, as OCNDS patients only have changes on one copy) do not survive long enough to be born. The authors go on to discuss the different ways each mutation might lead to dysfunction of the CK2 protein on a molecular level. Together, this paper defined for the first time that OCNDS is a neurodevelopmental disorder characterized by specific traits and is caused by mutations in the CSNK2A1 gene.