Summary
The dataset presents clinical and genetic evidence for CSNK2A1 haploinsufficiency impacting human disease, characterized through mutations in various patients indicating loss of function (LoF). Multiple cases depicted the presence of null or LoF mutations: Proband with 'c.967dupT, p.Tyr323Leufs*16', exhibiting developmental delays and other phenotypic abnormalities; Patient 26 encompassing 'p.R191*' mutation, phenotype unspecified; Patient 28 with 'c.1061-1G > C' splice variant, phenotype not detailed; Proband with p.Tyr323Leufs*16 variant, linked to seizures and limb weakness; Patient with 'p.H29Cfs*9', experiencing fewer neurodevelopmental concerns; and Patient with start codon mutation 'p.M1V', clinical profile not detailed, inheritance information unavailable for the last two. Functional studies employing transcription and gene expression analysis revealed reduced CSNK2A1 product or mRNA, consistent with haploinsufficiency and suggesting decreased protein levels due to nonsense-mediated decay in the case of the frameshift variant.
Evidence of Haploinsufficiency
Patient Identifier: proband
Mutation Type: frameshift
Mutation Details: c.967dupT, p.Tyr323Leufs*16 in exon 12
Clinical Phenotype: developmental delays, mild-to-moderate intellectual impairment, hypotonia, feeding challenges, distinctive facial features, speech delay
Inheritance Tested: Yes
Effect on Gene Function: A ∼50% decrease in the CSNK2A1 product
Direct Quote: "Sequence analysis revealed a c.967dupT, p.Tyr323Leufs*16 frameshift variant in exon 12 of CSNK2A1 in the proband and her mother. ... A ∼50% decrease in the CSNK2A1 product (normalized to β-actin level) was observed in the patient compared with the three wild-type control subjects."
Location in Paper: Clinical and genetic study subsection
Patient Identifier: 26
Mutation Type: nonsense mutation
Mutation Details: p.R191*
Clinical Phenotype: Not specified in the provided text
Inheritance Tested: Yes
Effect on Gene Function: Predicted to result in a truncated protein leading to loss of function
Direct Quote: "26 p.R191*"
Location in Paper: Case 26 evidence
Patient Identifier: 28
Mutation Type: canonical splice variants
Mutation Details: c.1061-1G > C
Clinical Phenotype: Not specified in the provided text
Inheritance Tested: Yes
Effect on Gene Function: Predicted to impair splicing leading to loss of function
Direct Quote: "28 c.1061-1G > C"
Location in Paper: Case 28 evidence
Patient Identifier: Proband with p.Tyr323Leufs*16 variant
Mutation Type: frameshift
Mutation Details: p.Tyr323Leufs*16
Clinical Phenotype: seizures, language impairment, and limb weakness
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause a loss of protein function
Direct Quote: "In this study, we present a novel frameshift variant, p.Tyr323Leufs*16, in an OCNDS family. The proband exhibited seizures, language impairment, and limb weakness."
Location in Paper: DISCUSSION
Patient Identifier: Patient with p.H29Cfs*9 pathogenic variant
Mutation Type: frameshift
Mutation Details: p.H29Cfs*9
Clinical Phenotype: well-controlled generalized seizure disorder with no neurodevelopmental concerns, brain MRI abnormalities, intellectual disability, or facial dysmorphisms
Inheritance Tested: No
Effect on Gene Function: predicted to cause a loss of protein function
Direct Quote: "This mirrors the phenotype of a patient with the p.H29Cfs*9 pathogenic variant in CSNK2A1, who displayed a well-controlled generalized seizure disorder with no neurodevelopmental concerns, brain MRI abnormalities, intellectual disability, or facial dysmorphisms (Wafik et al., 2023)."
Location in Paper: DISCUSSION
Patient Identifier: Patient with p.M1V variant
Mutation Type: start codon mutation
Mutation Details: p.M1V
Clinical Phenotype: clinical profile not detailed
Inheritance Tested: No
Effect on Gene Function: predicted to cause a loss of protein from Position 1 to 137
Direct Quote: "The p.M1V variant, affecting the start codon and predicted to cause a loss of protein from Position 1 to 137, where the next in-frame start codon is located, was classified as a null variant in this study (Chiu et al., 2018)."
Location in Paper: DISCUSSION
Clinical Features
Feature: reduced frequency of language deficits, dysmorphic facial features, or intellectual disability
Frequency: specific frequency not provided
Direct Quote: "We observed that individuals with CSNK2A1 null variants are less inclined to exhibit significant developmental and neurological symptoms when compared to those harboring missense variants. They display a significantly reduced frequency of symptoms associated with language deficits, dysmorphic facial features, or intellectual disability"
Location in Paper: Present study
Functional Studies
Study Type: Transcription analysis
Methodology: Agarose gel electrophoresis of long-range RT-PCR products, and Sanger sequencing of long-range RT-PCR products
Conclusions: The transcript with the frameshift variant was not detected, indicating potential nonsense-mediated decay and a resulting decrease in gene product.
Direct Quote: "Agarose gel electrophoresis of the long-range RT-PCR products revealed only the cDNA fragment of 1262 bp corresponding to the predicted canonical transcripts in the patient. ... The transcript with the frameshift variant was not detected."
Location in Paper: Clinical and genetic study subsection
Study Type: Gene expression analysis
Methodology: qRT-PCR using total RNA extracted from peripheral leukocytes
Conclusions: A ∼50% decrease in the CSNK2A1 product in the patient compared with wild-type control subjects, reflective of haploinsufficiency due to the frameshift variant.
Direct Quote: "CSNK2A1 gene expression was analyzed by qRT-PCR using total RNA extracted from peripheral leukocytes of the patient with primer sets corresponding to sequences within exons 8–10. A ∼50% decrease in the CSNK2A1 product (normalized to β-actin level) was observed in the patient compared with the same product in the three wild-type control subjects."
Location in Paper: Clinical and genetic study subsection
Study Type: Transcription analysis with RT-PCR and Agarose gel electrophoresis
Methodology: Performed reverse transcription polymerase chain reaction (RT-PCR) using total RNA from leukocytes of the proband. Agarose gel electrophoresis of the long-range RT-PCR products and Sanger sequencing from both directions.
Conclusions: The truncated transcript of CSNK2A1 may be significantly reduced due to NMD. No additional CSNK2A1 isoforms were found, making alternative splicing less likely. The expression of CSNK2A1 transcripts was decreased by approximately 0.5-fold in the patient compared to the three wild-type controls when normalized to the β-actin levels.
Direct Quote: "To analyze the mRNA expression affected by the variant c.967dupT in CSNK2A1, we performed reverse transcription polymerase chain reaction (RT-PCR) using total RNA from leukocytes of the proband."
Location in Paper: Section 3.3 Transcription analysis