Challenges in Clinicogenetic Correlations: One Phenotype - Many Genes

Area of Science:

• Genetics
• Neurology
• Bioinformatics

Background:

• The traditional
• one-phenotype-one-gene
• model in movement disorders is increasingly replaced by the
• one-phenotype-many-genes
• paradigm due to next-generation sequencing (NGS) advancements.
• This shift complicates genotype-phenotype correlations and genetic diagnostics.

Purpose of the Study:

• To review the challenges and propose solutions for the
• one-phenotype-many-genes
• paradigm in movement disorder diagnosis.
• To outline future directions for improving genetic diagnostic yield.

Main Methods:

• A scoping review was conducted to examine various aspects of identifying molecular causes for movement disorder phenotypes.

Main Results:

• Key challenges include lack of gold standards, overlapping clinical spectra, inconsistent classification, patient selection for genetic testing, variant interpretation issues, and incomplete gene lists.
• Proposed solutions involve deep phenotyping, genotype-phenotype integration, phenotype-specific algorithms, bioinformatic tools, and clinical-laboratory collaboration.

Conclusions:

• Next-generation sequencing (NGS) offers significant potential but requires further development to enhance genetic diagnostic yield in movement disorders.
• Future research should focus on post-NGS phenotyping, cohort analyses, genotype-phenotype integration, and gene networks to accelerate gene discovery and understand disease biology.