Challenges in Clinicogenetic Correlations : One Phenotype – Many Genes
(2021) In Movement Disorders Clinical Practice 8(3). p.311-321- Abstract
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... (More)
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.
(Less)
- author
- Gannamani, Rahul ; van der Veen, Sterre ; van Egmond, Martje ; de Koning, Tom J LU and Tijssen, Marina A J
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- movement disorder, phenotype, genotype, neurogenetics, genetics
- in
- Movement Disorders Clinical Practice
- volume
- 8
- issue
- 3
- pages
- 11 pages
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:33816658
- scopus:85101871247
- ISSN
- 2330-1619
- DOI
- 10.1002/mdc3.13163
- language
- English
- LU publication?
- yes
- id
- a5fbbb4f-6181-469b-bc99-67fb88077143
- date added to LUP
- 2021-03-13 18:14:23
- date last changed
- 2024-09-19 17:46:19
@article{a5fbbb4f-6181-469b-bc99-67fb88077143,
abstract = {{<p>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.</p><p>Objectives: To highlight the "one-phenotype-many-genes" paradigm by discussing the main challenges, perspectives on how to address them, and future directions.</p><p>Methods: We performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype.</p><p>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.</p><p>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.</p>}},
author = {{Gannamani, Rahul and van der Veen, Sterre and van Egmond, Martje and de Koning, Tom J and Tijssen, Marina A J}},
issn = {{2330-1619}},
keywords = {{movement disorder, phenotype, genotype, neurogenetics, genetics}},
language = {{eng}},
number = {{3}},
pages = {{311--321}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Movement Disorders Clinical Practice}},
title = {{Challenges in Clinicogenetic Correlations : One Phenotype – Many Genes}},
url = {{http://dx.doi.org/10.1002/mdc3.13163}},
doi = {{10.1002/mdc3.13163}},
volume = {{8}},
year = {{2021}},
}