Challenges in Clinicogenetic Correlations: One Gene - Many Phenotypes.

Area of Science:

• Genetics and Neurology
• Neurodegenerative Diseases
• Movement Disorders

Background:

• Next-generation sequencing (NGS) has advanced gene discovery, revealing complex genotype-phenotype correlations in movement disorders.
• Single gene mutations can manifest as diverse phenotypes, challenging clinicogenetic correlations for specialists.
• Understanding these complexities is vital for diagnosing and treating genetically heterogeneous neurological conditions.

Purpose of the Study:

• To deconstruct the biological phenomena and mechanistic bases of phenotypic heterogeneity in monogenic movement disorders and neurodegenerative diseases.
• To explore the evolving role of movement disorder specialists in the context of NGS and disease phenotype interpretation.
• To provide insights into managing genetically complex neurological disorders.

Main Methods:

• This study employed a scoping review methodology.
• Detailed examination of phenomena contributing to phenotypic heterogeneity in genetic disorders.
• Analysis of underlying genetic, epigenetic, and environmental mechanisms.

Main Results:

• Phenotypic heterogeneity in monogenic disorders is driven by incomplete penetrance, variable expressivity, and pleiotropy.
• Mechanisms include genetic factors (mutations, mosaicism, gene interactions), epigenetic factors (imprinting, X-inactivation), and environmental influences.
• These factors are often interconnected and not fully elucidated.

Conclusions:

• Movement disorders require significant clinical judgment for phenotype definition, a need amplified by NGS data.
• Deep phenotyping and understanding genotype-phenotype determinants are critical for accurate clinicogenetic correlations.
• These insights are essential for improved diagnosis, treatment, and genetic counseling in movement disorders.