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

Shalaw R Sallah¹, Panagiotis I Sergouniotis¹, Claire Hardcastle²

¹Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, United Kingdom.

The Journal of Molecular Diagnostics : JMD

|October 3, 2022

Summary

Structural analysis of in-frame indel variants in CACNA1F helps predict pathogenicity for X-linked incomplete congenital stationary night blindness type 2 (CSNB2). Disease-correlated variants destabilize the Ca_v1.4α1 channel, aiding CSNB2 diagnosis.

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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.