Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
22
10
2020
accepted:
05
02
2021
revised:
04
02
2021
pubmed:
19
3
2021
medline:
13
8
2021
entrez:
18
3
2021
Statut:
ppublish
Résumé
Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype-phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the Na We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype-phenotype correlations along a multidimensional spectrum.
Identifiants
pubmed: 33731876
doi: 10.1038/s41436-021-01120-1
pii: S1098-3600(21)05028-0
pmc: PMC8257493
doi:
Substances chimiques
NAV1.2 Voltage-Gated Sodium Channel
0
SCN2A protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1263-1272Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : K02 NS112600
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS091008
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS108874
Pays : United States
Organisme : Wellcome Trust
ID : 203914/Z/16/Z
Pays : United Kingdom
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