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

TitleHeterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsMeester 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
JournalAm J Hum Genet
Volume97
Issue3
Pagination475-82
Date Published2015 Sep 03
ISSN1537-6605
KeywordsAmino 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
Abstract<p>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.</p>
DOI10.1016/j.ajhg.2015.07.015
Alternate JournalAm. J. Hum. Genet.
PubMed ID26299364
PubMed Central IDPMC4564989
Grant ListP50 GM076547 / GM / NIGMS NIH HHS / United States
GM076547 / GM / NIGMS NIH HHS / United States