TY - JOUR
T1 - Challenges in Clinicogenetic Correlations
T2 - One Phenotype – Many Genes
AU - Gannamani, Rahul
AU - van der Veen, Sterre
AU - van Egmond, Martje
AU - de Koning, Tom J.
AU - Tijssen, Marina A.J.
N1 - Funding Information:
Tom J. de Koning reports grants from the Metabolic Power Foundation, the Piet Poortman Foundation, and the North Sea Myoclonus Foundation. Marina A.J. Tijssen reports grants from the Netherlands Organization for Health Research and Development ZonMW Topsubsidie (91218013), the European Fund for Regional Development from the European Union (01492947), and the province of Friesland, Dystonia Medical Research Foundation, Stichting Wetenschapsfonds Dystonie Vereniging, Fonds Psychische Gezondheid, and Phelps Stichting and an unrestricted grant from Actelion and AOP Orphan Pharmaceuticals AG.
Publisher Copyright:
© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - genetics
KW - genotype
KW - movement disorder
KW - neurogenetics
KW - phenotype
U2 - 10.1002/mdc3.13163
DO - 10.1002/mdc3.13163
M3 - Review article
AN - SCOPUS:85101871247
SN - 2330-1619
VL - 8
SP - 311
EP - 321
JO - Movement Disorders Clinical Practice
JF - Movement Disorders Clinical Practice
IS - 3
ER -