Assessing the Pathogenicity of In-Frame CACNA1F Indel Variants Using Structural Modeling

Area of Science:

• Genomics
• Structural Biology
• Ophthalmology

Background:

• Small in-frame insertion-deletion (indel) variants are common genomic variations.
• Their impact on rare disease phenotypes, particularly CSNB2, is understudied.
• Predicting the pathogenicity of these indel variants is challenging.

Purpose of the Study:

• To interpret the pathogenicity of in-frame indel variants in CACNA1F using structural analysis.
• To investigate the structural and functional consequences of disease-correlated and benign variants.
• To improve diagnostic capabilities for CSNB2.

Main Methods:

• Homology modeling was employed for structural analysis of CACNA1F variants.
• 10 disease-correlated and 10 putatively benign in-frame indel variants were analyzed.
• Conservation analysis and assessment of variant location within modeled protein regions were performed.

Main Results:

• CSNB2-correlated variants exhibited higher conservation than benign variants.
• All disease-correlated variants were located within modeled regions of the Ca_v1.4α1 channel protein.
• Disease-correlated variants are predicted to destabilize the channel's structure and function.

Conclusions:

• Structural analysis of in-frame indel variants provides valuable insights into pathogenicity.
• This approach can enhance the diagnosis of CSNB2.
• Interpreting indel variant consequences through structural information is a key adjunct for rare disease diagnosis.