Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome

Adams-Oliver syndrome (AOS, OMIM; 100300) is a rare genetic disease characterized by aplasia cutis congenita, terminal transverse limb defects and cutis marmorata with vascular anomalies such as congenital heart defects. The etiology of this syndrome has remained largely unknown but defective Notch signaling during vascular formation has been suggested. Here we describe a sporadic Japanese newborn case with clinically diagnosed AOS. Trio whole-exome sequencing identified a de novo, novel, heterozygous missense mutation in the Delta-like 4 ligand gene (DLL4 c.572G>A, p.Arg191His) in the patient. DLL4 functions as a requisite ligand for NOTCH1 receptor, which is essential for vascular formation. Amino acid substitution of Arg191 to His was predicted by molecular models to interfere with direct binding between DLL4 and NOTCH1. DLL4 has recently been identified as a causative gene of an autosomal dominant type of AOS with milder symptoms. The case described here showed gradual recovery from skull defects after birth and no psychomotor developmental delay has been observed. This is the second report of an AOS case with DLL4 mutation, and the phenotypic characteristics between the two cases are compared and discussed.