Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver Syndrome.

TitleHeterozygous loss-of-function mutations in DLL4 cause Adams-Oliver Syndrome.
Publication TypeConference Paper
Year of Publication2015
AuthorsMeester JAN, Southgate L, Stittrich AB, 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
Conference NameAmerican Society for Human Genetics
Date Published10/2015
Type of WorkAbstract
AbstractAdams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of both aplasia cutis congenita (ACC) of the scalp vertex and terminal limb reduction defects, such as brachydactyly, oligodactyly, syndactyly, hypoplastic nails or transverse amputations. Cardiovascular anomalies, comprising pulmonary hypertension, ventricular septum defects, tetralogy of Fallot and anomalies of the great arteries and their valves 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 the autosomal dominant form of AOS. As RBPJ, NOTCH1 and EOGT are all involved in the Notch signaling cascade, we hypothesized that mutations in other genes involved in this pathway may 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 and angiogenesis in the context of cardiovascular features in AOS patients. Targeted resequencing of the DLL4 gene using a custom enrichment panel was performed in 89 independent families, in which we found seven mutations. In addition, a defect in DLL4 was also detected in two pedigrees with whole exome/genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense variants, which are predicted to lead to nonsense mediated decay, and seven missense variants. These missense variants encompass four mutations that replace or create cysteine residues, which are likely critical for maintaining the structural integrity of the protein and three mutations that affect conserved amino acids in two functional domains of the protein. These functional domains include the DSL domain and the MNNL domain, which are both involved in binding of the ligand to the Notch receptor. Affected individuals with DLL4 mutations present with variable clinical expression and incomplete penetrance with no emerging genotype-phenotype correlations. Our findings demonstrate DLL4 mutations as an additional cause of autosomal dominant AOS or isolated ACC and provide yet further evidence for a key role of Notch signaling in the etiology of this disorder.