Summary
This compilation of clinical genetic evidence focuses on the CSNK2A1 gene and its role in disease through haploinsufficiency. Two patients were investigated for their clinical phenotypes associated with frameshift and missense variants identified by sequencing technologies. Patient 1 exhibits a de novo CSNK2A1 frameshift variant leading to significant failure to thrive and behavioral feeding problems, with no associated learning difficulties or confirmed inheritance due to testing not performed. Additionally, a missense variant (NM_177559.3:c.142G>A (p.Gly48Ser)) in the same patient correlates with inattention and lack of academic focus; inheritance was confirmed as de novo. In the second case, a frameshift variant (p.(His29CysfsTer9)) involves generalized tonic-clonic seizures, coordination difficulties, and normal speech acquisition; the inheritance is confirmed as de novo. Another report on patient 1, possibly a different clinical manifestation or an incomplete dataset, describes a heterozygous frameshift variant (NM_177559.3:c.85_86delCA) causing seizures and motor delay, with inheritance information unavailable. For patient 2, the same frameshift mutation is noted, presenting notably with seizures and no distinctive features, and also without inheritance information. Functional studies are lacking, making it difficult to assert the exact impact of variants on protein function, but multiple cases indicate predicted loss-of-function as key findings supporting haploinsufficiency of CSNK2A1.
Evidence of Haploinsufficiency
Patient Identifier: Patient 1
Mutation Type: frameshift
Mutation Details: a de novo CSNK2A1 frameshift variant
Clinical Phenotype: significant failure to thrive and behavioural feeding problems, food-aversive behaviors with a reluctance to eat solid food or feed himself
Inheritance Tested: No
Effect on Gene Function: suggesting haploinsufficiency as a potential disease mechanism
Direct Quote: "We also report a case of OCNDS caused by a de novo CSNK2A1 frameshift variant with no associated learning difficulties."
Location in Paper: Clinical report Patient 1
Patient Identifier: Patient 1
Mutation Type: missense variant
Mutation Details: NM_177559.3:c.142G>A (p.Gly48Ser) in CSNK2A1
Clinical Phenotype: Inattention, lack of focus, 12 months behind peers academically
Inheritance Tested: Yes
Effect on Gene Function: Glycine at residue 48 is well-conserved, suggesting that a missense alteration may impair gene function
Direct Quote: "Sequence analysis identified a heterozygous missense variant at NM_177559.3:c.142G>A (p.Gly48Ser) in CSNK2A1. Follow-up parental testing by Sanger sequencing (Fig. 2c) confirmed that the variant was absent from both maternal and paternal samples. Parental relationships were confirmed by quantitative fluorescent PCR."
Location in Paper: Wafik et al. 119
Patient Identifier: Patient 2
Mutation Type: frameshift variant
Mutation Details: p.(His29CysfsTer9) in CSNK2A1
Clinical Phenotype: Generalised tonic-clonic seizures, coordination difficulties, delayed motor milestones, speech achieved on time, no academic concerns
Inheritance Tested: Yes
Effect on Gene Function: Frameshift likely results in loss-of-function due to early truncation of the protein
Direct Quote: "p.(His29CysfsTer9) in CSNK2A1 and a heterozygous missense variant NM_001134407.1:c.649G>T p.(Val217Phe) in GRIN2A. The CSNK2A1 variant was not detected in the maternal or paternal samples, with confirmed parental relationships."
Location in Paper: Wafik et al. 119
Patient Identifier: patient 1
Mutation Type: heterozygous frameshift variant
Mutation Details: NM_177559.3:c.85_86delCA
Clinical Phenotype: febrile seizures, generalised tonic-clonic seizures, motor delay, coordination difficulties, normal growth parameters, no distinctive facial or physical features, absence seizures
Inheritance Tested: No
Effect on Gene Function: frameshift variant predicted to result in a loss of function of the CSNK2A1 gene
Direct Quote: "Singleton sequence analysis identified a heterozy- gous frameshift variant NM_177559.3:c.85_86delCA"
Location in Paper: The mutation details: 'Singleton sequence analysis identified a heterozy- gous frameshift variant NM_177559.3:c.85_86delCA.' The clinical phenotype: 'She presented with her first febrile seizure aged 4 years, ...', '...but there were some concerns about potential ongoing absence seizures.'
Patient Identifier: patient 2
Mutation Type: frameshift
Mutation Details: p.(His29CysfsTer9)
Clinical Phenotype: No distinctive facial or physical features were noted.
Inheritance Tested: Yes
Effect on Gene Function: variant is predicted to produce an out of frame transcript resulting in premature truncation of the CSNK2A1 transcript
Direct Quote: "For patient 2, the CSNK2A1 p.(His29CysfsTer9) variant is absent from gnomAD (PM2_Supporting) and occurred de novo in the proband (PS2_Supporting)."
Location in Paper: Clinical and molecular features observed in patient 2
Patient Identifier: Patient 2
Mutation Type: frameshift variant
Mutation Details: p.(His29CysfsTer9)
Clinical Phenotype: a predominantly seizure disorder
Inheritance Tested: No
Effect on Gene Function: Predicted to impair gene function due to frameshift mutation leading to a premature termination codon
Direct Quote: "Patient 2, who presented with a predominantly seizure disorder, harboured a rare CNSK2A1 frameshift variant, p.(His29CysfsTer9)."
Location in Paper: Patient 2 description
Clinical Features
Feature: GDD/ID, short stature, and microcephaly
Frequency: Not specified
Direct Quote: "Patient 1 presented with non-specific clinical features such as GDD/ID, short stature, and microcephaly (Table 1)."
Location in Paper: Discussion
Feature: predominantly seizure disorder
Frequency: Not specified
Direct Quote: "Patient 2, who presented with a predominantly seizure disorder, harboured a rare CNSK2A1 frameshift variant, p.(His29CysfsTer9)."
Location in Paper: Discussion
Functional Studies
Study Type: Not available
Methodology: Not available
Conclusions: It is challenging to predict the variant’s effect on the expressed protein without available functional data
Direct Quote: "It is challenging to predict the variant’s effect on the expressed protein without available functional data"
Location in Paper: Discussion