Challenges in Clinicogenetic Correlations: One Phenotype – Many Genes

BACKGROUND: In the field of movement disorders, what you see (phenotype) is seldom what you get (genotype). Whereas 1 phenotype was previously associated to 1 gene, the advent of next‐generation sequencing (NGS) has facilitated an exponential increase in disease‐causing genes and genotype–phenotype correlations, and the “one‐phenotype‐many‐genes” paradigm has become prominent. OBJECTIVES: To highlight the “one‐phenotype‐many‐genes” paradigm by discussing the main challenges, perspectives on how to address them, and future directions. METHODS: We performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype. RESULTS: The notable challenges are (1) the lack of gold standards, overlap in clinical spectrum of different movement disorders, and variability in the interpretation of classification systems; (2) selecting which patients benefit from genetic tests and the choice of genetic testing; (3) problems in the variant interpretation guidelines; (4) the filtering of variants associated with disease; and (5) the lack of standardized, complete, and up‐to‐date gene lists. Perspectives to address these include (1) deep phenotyping and genotype–phenotype integration, (2) adherence to phenotype‐specific diagnostic algorithms, (3) implementation of current and complementary bioinformatic tools, (4) a clinical‐molecular diagnosis through close collaboration between clinicians and genetic laboratories, and (5) ongoing curation of gene lists and periodic reanalysis of genetic sequencing data. CONCLUSIONS: Despite the rapidly emerging possibilities of NGS, there are still many steps to take to improve the genetic diagnostic yield. Future directions, including post‐NGS phenotyping and cohort analyses enriched by genotype–phenotype integration and gene networks, ought to be pursued to accelerate identification of disease‐causing genes and further improve our understanding of disease biology.