Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
01
02
2020
accepted:
28
07
2020
revised:
24
07
2020
pubmed:
15
8
2020
medline:
27
1
2022
entrez:
15
8
2020
Statut:
ppublish
Résumé
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
Identifiants
pubmed: 32792659
doi: 10.1038/s41380-020-0858-6
pii: 10.1038/s41380-020-0858-6
pmc: PMC8505254
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
Banques de données
ClinicalTrials.gov
['NCT00296764']
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
3625-3633Subventions
Organisme : NICHD NIH HHS
ID : U54 HD061222
Pays : United States
Organisme : NCRR NIH HHS
ID : U54 RR019478
Pays : United States
Informations de copyright
© 2020. The Author(s).
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