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

Am J Hum Genet. 2015 Sep 3;97(3):475-82. doi: 10.1016/j.ajhg.2015.07.015.

Josephina A N Meester ¹, Laura Southgate ², Anna-Barbara Stittrich ³, Hanka Venselaar ⁴, Sander J A Beekmans ⁵, Nicolette den Hollander ⁶, Emilia K Bijlsma ⁶, Appolonia Helderman-van den Enden ⁶, Joke B G M Verheij ⁷, Gustavo Glusman ³, Jared C Roach ³, Anna Lehman ⁸, Millan S Patel ⁸, Bert B A de Vries ⁹, Claudia Ruivenkamp ⁶, Peter Itin ¹⁰, Katrina Prescott ¹¹, Sheila Clarke ¹², Richard Trembath ², Martin Zenker ¹³, Maja Sukalo ¹³, Lut Van Laer ¹, Bart Loeys ¹⁴, Wim Wuyts ¹⁵

Affiliations

1 Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium.
2 Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
3 Institute for Systems Biology, Seattle, Washington, SA 98109, USA.
4 Centre of Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, 6525 GA, the Netherlands.
5 Department of Plastic and Reconstructive Surgery, VU Medical Center Amsterdam, Amsterdam, 1081 HZ, the Netherlands.
6 Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands.
7 Department of Medical Genetics, University Medical Centre Groningen and University of Groningen, Groningen, 9700 RB, the Netherlands.
8 Department of Medical Genetics, Child and Family Research Institute and University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
9 Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, 6500 HB, the Netherlands.
10 Department of Dermatology, University Hospital of Basel, Basel, 4031, Switzerland.
11 Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
12 Department of Dermatology, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
13 Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg and University Hospital Magdeburg, Magdeburg, 39120, Germany.
14 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: [email protected].
15 Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, 2650, Belgium. Electronic address: [email protected].

PMID: 26299364 DOI: 10.1016/j.ajhg.2015.07.015

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.

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