DLL4 – Adams-Oliver Syndrome

Multiple independent studies provide strong evidence linking heterozygous mutations in DLL4 to Adams-Oliver syndrome. In several case reports, de novo missense mutations (e.g., 1 proband with c.82G>C (p.Gly28Arg) (PMID:34755929)) have been identified in patients presenting with hallmark features such as aplasia cutis congenita and vascular anomalies. Furthermore, additional cases have reported de novo and familial occurrences of missense variants (including c.572G>A (p.Arg191His) in a Japanese case (PMID:28446798)) thereby strongly supporting the gene–disease association.

Genetic evidence is bolstered by multi‑patient studies where targeted resequencing identified multiple heterozygous mutations in DLL4 across independent families (PMID:26299364). These studies report a spectrum of variant types including loss‑of‑function, nonsense, and missense alterations, which collectively implicate disrupted Notch signaling in the disorder. Segregation analyses in these families further reinforce the autosomal dominant inheritance pattern, with affected relatives demonstrating concordant segregation of the pathogenic variants.

Functional studies further support the role of DLL4 in the pathogenesis of Adams-Oliver syndrome. In vitro assays and animal models have demonstrated that DLL4 is a critical ligand in the Notch signaling pathway, essential for proper vascular development. Disruption of DLL4 function due to pathogenic variants has been shown to alter vascular morphogenesis, consistent with the vascular phenotypes observed in affected patients (PMID:26299364).

The combined genetic and functional data coalesce into a coherent narrative: pathogenic mutations in DLL4 lead to aberrant Notch signaling, resulting in the clinical manifestations of scalp and limb defects as seen in Adams-Oliver syndrome. Although additional evidence exists from studies with broader phenotypic assessments, the current data are sufficient to support a strong gene–disease relationship.

This evidence not only substantiates the diagnostic utility of genetic testing for DLL4 mutations in patients with Adams-Oliver syndrome but also highlights the clinical relevance for tailored management. Moreover, these findings offer commercial and research avenues for diagnostic assay development and further exploration into targeted therapies.

Key Take‑home sentence: Robust genetic and functional data affirm that DLL4 mutations disrupt Notch signaling, establishing a strong, clinically actionable association with Adams-Oliver syndrome.

References

• American journal of medical genetics. Part A • 2022 • A novel DLL4 mutation in Adams-Oliver syndrome with absence of the right pulmonary artery in newborn PMID:34755929
• Journal of human genetics • 2017 • Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome PMID:28446798
• American journal of human genetics • 2015 • Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome PMID:26299364
• Frontiers in pediatrics • 2025 • Case Report: A novel DLL4 variant in a neonate with Adams-Oliver syndrome PMID:40098638

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