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MITOCHONDIRAS - Coggle Diagram
MITOCHONDIRAS
HETEROPLASMY
CHALLENGES
CONFIRMATION OF LOW-LEVEL HETEROPLASMY
Validation of subtle variations
Avoiding sequencing artifacts
ABSENCE OF CONSENSUS THERSHOLD
Lack of universally accepted level
Variation based on technology
CLINICAL RELEVANCE
VARIABILITY IN DIFFERENT TISSUES
Heteroplasmy levels vary among tissues
Influences clinical presentation
ESTIMATION TOOLS
Quantification in muscle based on blood or uroepithelial cells
Facilitates clinical interpretation
Example: (m.3243A>G)
THRESHOLD EFFECT ON CLINICAL IMPACT
Clinical manifestation linked to specific heteroplasmy levels
IMPACT ON CLINICAL PHENOTYPE
Influence of copy number changes on clinical outcome
Explains phenotypic variability
IMPROVED DETECTION
LOW-LEVEL mtDNA VARIATION
Detection of minor mutations
Substantial clinical relevance
DETECTION LIMITS
NGS, pyrosequencing capabilities
Improvement over Sanger sequencing
ENCHANCED SENSITIVITY
Duplex sequencing
Detects heteroplasmy down to 0.01%
IN SILCO PREDICTION TOOLS
CHALLENGES
HETEROPLASMY COMPLEXITY
Varied leves in different tissues
Influences clinical presentation
LIMITED GUIDELINES
Scarcity of standard criteria
Comparative challenges with nuclear VUS
NOVEL mtDNA VUS
DIverse, uncharacterized variants
Increased diagnostic complexity
TOOLS
NEW SPECIALIZED TOOLS
MToolBox, APOGEE, Mitoclass.1
Enhanced accuracy for mtDNA
SCORING APPROACHES
Integration of structure, conservation, function
Improved variant prioritization
VARYING PERFORMANCE
Discrepancies for mtDNA variants
Inaccuracies for mtDNA variants
ONGOING GUIDELINE DEVELOPMENT
Collaboration for mtDNA-specific guidelines
Harmonizing variant interpretation
EVALUATE mtDNA VARIANTS
Predict pathogenecity
Assess functional impact