Summary
This study presented evidence for haploinsufficiency of the CSNK2A1 gene in association with neurodevelopmental disabilities and dysmorphic features. Five patients were identified to harbor novel, de novo heterozygous variants, including one splice site variant (c.824+2T>C) and four missense variants (p.R47Q, p.Y50S, p.D175G, p.K198R), which are predicted to be deleterious by in silico models such as SIFT, Mutation Taster, Provean, and CADD. Clinical phenotypes of these patients prominently featured neurodevelopmental delays and dysmorphic facial features, with most patients exhibiting additional symptoms such as intellectual disability, behavioral problems, hypotonia, speech and gastrointestinal problems, with a subset also manifesting microcephaly, pachygyria, musculoskeletal, and immunologic issues. These variants were confirmed as de novo and inheritance testing was performed, indicating their likely contribution to the disease phenotype. Complementary functional studies in animal models, specifically conditional CK2α knock-out mice, demonstrated embryonic lethality and severe abnormalities when homozygous, and a 13% incidence of neural tube closure failure in heterozygous embryos, supporting the hypothesis that CSNK2A1 haploinsufficiency plays a significant role in human developmental disorders.
Evidence of Haploinsufficiency
Patient Identifier: No patient identifiers given
Mutation Type: missense variants, splice site variant
Mutation Details: p.R47Q, p.Y50S, p.D175G, p.K198R, c.824+2T>C
Clinical Phenotype: neurodevelopmental disabilities and dysmorphic features
Inheritance Tested: Yes
Effect on Gene Function: predicted to be deleterious by multiple prediction algorithms including SIFT, Mutation Taster, Provean, and CADD; predicted to disrupt proper splicing, suggesting loss of function could be the mechanism.
Direct Quote: "We present five patients with neurodevelopmental disabilities and dysmorphic features in whom we identified five different de novo novel variants in CSNK2A1. ... Five unrelated patients were found to have five different novel, de novo heterozygous variants in CSNK2A1 including one splice site variant (c.824+2T>C) and four missense variants (p.R47Q, p.Y50S, p.D175G, p.K198R) that are predicted to be deleterious...; Patients from five independent families with overlapping neurodevelopmental disorders and dysmorphic features were found to have likely damaging de novo splice site....site of intron 10, c.824+2T>C, that is predicted to disrupt proper splicing."
Location in Paper: Results, Discussion
Clinical Features
Feature: developmental delay
Frequency: 5/5
Direct Quote: "Features common to the majority of the probands include developmental delay (5/5)"
Location in Paper: Results
Feature: intellectual disability
Frequency: 4/5
Direct Quote: "intellectual disability (4/5)"
Location in Paper: Results
Feature: behavioral problems
Frequency: 4/5
Direct Quote: "behavioral problems (4/5)"
Location in Paper: Results
Feature: hypotonia
Frequency: 4/5
Direct Quote: "hypotonia (4/5)"
Location in Paper: Results
Feature: speech problems
Frequency: 4/5
Direct Quote: "speech problems (4/5)"
Location in Paper: Results
Feature: gastrointestinal problems
Frequency: 4/5
Direct Quote: "gastrointestinal problems (4/5)"
Location in Paper: Results
Feature: dysmorphic facial features
Frequency: 4/5
Direct Quote: "dysmorphic facial features (4/5)"
Location in Paper: Results
Feature: microcephaly
Frequency: 3/5
Direct Quote: "microcephaly (3/5)"
Location in Paper: Results
Feature: pachygyria
Frequency: 3/5
Direct Quote: "pachygyria observed on brain MRI (3/5)"
Location in Paper: Results
Feature: musculoskeletal problems
Frequency: 3/5
Direct Quote: "musculoskeletal (3/5)"
Location in Paper: Results
Feature: immunologic problems
Frequency: 3/5
Direct Quote: "immunologic (3/5) problems"
Location in Paper: Results
Functional Studies
Study Type: Animal model
Methodology: Studies with conditional knock-outs of CK2α in mice
Conclusions: Mice with homozygous deficiencies of CK2α were embryonic lethal with severe embryonic abnormalities. Among the heterozygotes, 13 % of the embryos had failure of neural tube closure suggesting a possible role of CSNK2A1 haploinsufficiency in development.
Direct Quote: "In studies with conditional knock-outs of CK2α, mice with homozygous deficiencies of CK2α (CK2α−−) were embryonic lethal with severe embryonic abnormalities, especially in the heart and neural tube.... Among the heterozygotes, 13 % of the embryos were noted to have failure of neural tube closure."
Location in Paper: Discussion