Challenges in Clinicogenetic Correlations: One Phenotype – Many Genes

Rahul Gannamani, Sterre van der Veen, Martje van Egmond, Tom J. de Koning, Marina A.J. Tijssen*

*Bijbehorende auteur voor dit werk

Onderzoeksoutputpeer review

12 Citaten (Scopus)
52 Downloads (Pure)


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.

Originele taal-2English
Pagina's (van-tot)311-321
Aantal pagina's11
TijdschriftMovement Disorders Clinical Practice
Nummer van het tijdschrift3
StatusPublished - apr.-2021

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