Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders.
DLL1
Notch signaling
autism
brain malformation
developmental delay
intellectual disability
vertebral segmentation defects
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
17
05
2019
accepted:
03
07
2019
pmc-release:
05
03
2020
pubmed:
30
7
2019
medline:
3
4
2020
entrez:
30
7
2019
Statut:
ppublish
Résumé
Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.
Identifiants
pubmed: 31353024
pii: S0002-9297(19)30265-4
doi: 10.1016/j.ajhg.2019.07.002
pmc: PMC6731356
pii:
doi:
Substances chimiques
Calcium-Binding Proteins
0
DLK1 protein, human
0
Ligands
0
Membrane Proteins
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
631-639Subventions
Organisme : NINDS NIH HHS
ID : K08 NS092898
Pays : United States
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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