ACO2 clinicobiological dataset with extensive phenotype ontology annotation

Area of Science:

• Genetics and Genomics
• Neuroscience
• Ophthalmology

Background:

• Pathogenic variants in the aconitase 2 gene (ACO2) are linked to optic nerve degeneration.
• These variants can cause isolated optic neuropathy or complex neurodegenerative syndromes.
• Current classifications may not fully capture the spectrum of ACO2-related disorders.

Purpose of the Study:

• To establish the first public locus-specific database (LSDB) for ACO2 variants.
• To utilize the Human Phenotype Ontology (HPO) for standardized phenotypic descriptions.
• To analyze the clinical spectrum and refine variant classifications for ACO2.

Main Methods:

• Creation of a dedicated ACO2 LSDB within the Global Variome shared LOVD platform.
• Inclusion of all reported ACO2 variants and clinical cases from existing literature.
• Application of a systematic approach using the HPO thesaurus for data analysis.

Main Results:

• Demonstrated that ACO2-related conditions represent a continuum of symptoms rather than distinct isolated or syndromic cases.
• Identified syndromic patients lacking optic neuropathy, challenging traditional classifications.
• Provided evidence supporting the classification of recurrent variants c.220C>G and c.336C>G as likely pathogenic.

Conclusions:

• The clinical spectrum of ACO2 variants is broader and more continuous than previously understood.
• Standardized phenotyping using HPO refines the classification of ACO2-related disorders.
• This work enhances understanding and classification of ACO2 pathogenic variants and their associated phenotypes.