Publication
Title
Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver Syndrome
Author
Abstract
Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because REP]; NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.
Language
English
Source (journal)
The American journal of human genetics / American Society of Human Genetics [Bethesda, Md] - New York, N.Y., 1949, currens
Publication
New York, N.Y. : 2015
ISSN
0002-9297 [print]
1537-6605 [online]
DOI
10.1016/J.AJHG.2015.07.015
Volume/pages
97 :3 (2015) , p. 475-482
ISI
000361084700010
Pubmed ID
26299364
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Project info
Clinical and (patho)genetic study of bicuspid aortic valve and associated aortic aneurysm.
Application of whole exome sequencing to identify the genetic defect in hereditary connective tissue disorders
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 05.10.2015
Last edited 09.10.2023
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