Variant pathogenicity evaluation in the community-driven Inherited Neuropathy Variant Browser

Area of Science:

• Genetics
• Neurology
• Bioinformatics

Background:

• Charcot-Marie-Tooth disease (CMT) encompasses over 120 identified genes, leading to a high prevalence of variants of uncertain clinical significance (VUS) in genetic testing.
• The increasing number of VUS poses significant challenges for genetic counseling and diagnosis.
• Limited publication of individual gene variants and lack of phenotype correlation in clinical testing further complicate interpretation.

Purpose of the Study:

• To establish a centralized, open-access resource for capturing and sharing genetic variation data in CMT genes.
• To facilitate the interpretation of genetic variants by providing a comprehensive collection of alleles and associated phenotypic information.
• To encourage global participation from researchers and clinicians in contributing to a robust CMT variant database.

Main Methods:

• Development of the Inherited Neuropathy Variant Browser, a user-friendly platform for data submission and access.
• Aggregation of genetic variation data from published literature, clinical testing, and research studies.
• Bi-annual submission of aggregated data to ClinVar for wider accessibility.

Main Results:

• The Inherited Neuropathy Variant Browser offers open access to reported variations in CMT genes.
• The platform allows geneticists, physicians, and genetic counselors to submit and access variant data, including phenotypic correlations.
• The initiative aims to build a large collection of CMT alleles, enhancing diagnostic capabilities.

Conclusions:

• The Inherited Neuropathy Variant Browser represents a significant advancement in managing and interpreting CMT genetic variation.
• Active community participation is crucial for the resource's growth and its impact on clinical genetic counseling for CMT.
• This collaborative approach will improve the understanding and diagnosis of inherited neuropathies.