title: Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.
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.
authors: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium.
authors: Josephina A N
authors: JA
authors: Meester
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Laura
authors: L
authors: Southgate
authors: Institute for Systems Biology, Seattle, Washington, SA 98109, USA.
authors: Anna-Barbara
authors: AB
authors: Stittrich
authors: Centre of Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, 6525 GA, the Netherlands.
authors: Hanka
authors: H
authors: Venselaar
authors: Department of Plastic and Reconstructive Surgery, VU Medical Center Amsterdam, Amsterdam, 1081 HZ, the Netherlands.
authors: Sander J A
authors: SJ
authors: Beekmans
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands.
authors: Nicolette
authors: N
authors: den Hollander
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands.
authors: Emilia K
authors: EK
authors: Bijlsma
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands.
authors: Appolonia
authors: A
authors: Helderman-van den Enden
authors: Department of Medical Genetics, University Medical Centre Groningen and University of Groningen, Groningen, 9700 RB, the Netherlands.
authors: Joke B G M
authors: JB
authors: Verheij
authors: Institute for Systems Biology, Seattle, Washington, SA 98109, USA.
authors: Gustavo
authors: G
authors: Glusman
authors: Institute for Systems Biology, Seattle, Washington, SA 98109, USA.
authors: Jared C
authors: JC
authors: Roach
authors: Department of Medical Genetics, Child and Family Research Institute and University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
authors: Anna
authors: A
authors: Lehman
authors: Department of Medical Genetics, Child and Family Research Institute and University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
authors: Millan S
authors: MS
authors: Patel
authors: Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, 6500 HB, the Netherlands.
authors: Bert B A
authors: BB
authors: de Vries
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands.
authors: Claudia
authors: C
authors: Ruivenkamp
authors: Department of Dermatology, University Hospital of Basel, Basel, 4031, Switzerland.
authors: Peter
authors: P
authors: Itin
authors: Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
authors: Katrina
authors: K
authors: Prescott
authors: Department of Dermatology, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
authors: Sheila
authors: S
authors: Clarke
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Richard
authors: R
authors: Trembath
authors: Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg and University Hospital Magdeburg, Magdeburg, 39120, Germany.
authors: Martin
authors: M
authors: Zenker
authors: Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg and University Hospital Magdeburg, Magdeburg, 39120, Germany.
authors: Maja
authors: M
authors: Sukalo
authors: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium.
authors: Lut
authors: L
authors: Van Laer
authors: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium; Department of Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands. Electronic address: bart.loeys@uantwerpen.be.
authors: Bart
authors: B
authors: Loeys
authors: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium. Electronic address: wim.wuyts@uantwerpen.be.
authors: Wim
authors: W
authors: Wuyts
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D051880:Receptors, Notch / Q000235:genetics; D012536:Scalp Dermatoses / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch