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Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.

Meester, JAN; Southgate, L; Stittrich, A-B; Venselaar, H; Beekmans, SJA; den Hollander, N; Bijlsma, EK; Helderman-van den Enden, A; Verheij, JBGM; Glusman, G; et al. Meester, JAN; Southgate, L; Stittrich, A-B; Venselaar, H; Beekmans, SJA; den Hollander, N; Bijlsma, EK; Helderman-van den Enden, A; Verheij, JBGM; Glusman, G; Roach, JC; Lehman, A; Patel, MS; de Vries, BBA; Ruivenkamp, C; Itin, P; Prescott, K; Clarke, S; Trembath, R; Zenker, M; Sukalo, M; Van Laer, L; Loeys, B; Wuyts, W (2015) Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome. Am J Hum Genet, 97 (3). pp. 475-482. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2015.07.015
SGUL Authors: Southgate, Laura

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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 RBPJ, 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.

Item Type: Article
Additional Information: © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Amino Acid Sequence, Base Sequence, Ectodermal Dysplasia, Heterozygote, Humans, Intercellular Signaling Peptides and Proteins, Limb Deformities, Congenital, Molecular Sequence Data, Mutation, Pedigree, Receptors, Notch, Scalp Dermatoses, Sequence Analysis, DNA, Signal Transduction, Humans, Limb Deformities, Congenital, Ectodermal Dysplasia, Scalp Dermatoses, Intercellular Signaling Peptides and Proteins, Pedigree, Sequence Analysis, DNA, Signal Transduction, Amino Acid Sequence, Base Sequence, Heterozygote, Mutation, Molecular Sequence Data, Receptors, Notch, 06 Biological Sciences, 11 Medical And Health Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
3 September 2015Published
20 August 2015Published Online
29 July 2015Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
P50 GM076547NIGMS NIH HHSUNSPECIFIED
GM076547NIGMS NIH HHSUNSPECIFIED
PubMed ID: 26299364
Web of Science ID: WOS:000361084700010
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110213
Publisher's version: https://doi.org/10.1016/j.ajhg.2015.07.015

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