Current opinion in the molecular genetics of Adams-Oliver syndrome

ABSTRACT

Introduction: Adams–Oliver syndrome (AOS) is an orphan disorder of terminal transverse limb defects and aplasia cutis congenita, hypothesized to occur as a consequence of disordered vasculogenesis. AOS is estimated to affect 1 in 225,000 live births; however, comprehensive studies of geographical prevalence remain limited.

Areas covered: This review summarizes current opinion in the molecular genetics of AOS and provides recommended updates to the diagnostic criteria. Understanding of the clinical features associated with AOS has been much improved due to recent advancement in establishing the underlying genetic causes of the condition. To date, six causal genes have been described, which together specifically implicate Rho GTPase dysregulation and perturbed Notch signaling as central to disease development. Despite these genetic advances, mutations in the established genes only represent 36% of reported AOS cases, indicating a large degree of missing heritability still to be resolved. Furthermore, the fundamental mechanisms underlying AOS remain undefined, impeding diagnostic and treatment progression.

Expert opinion: Further work to examine structural variation and identify novel genes is necessary to explain the missing heritability in AOS. In the future, dedicated functional analyses will be required to delineate the pathogenic mechanisms and facilitate focused evaluation of targeted therapies.

KEYWORDS:

• Adams–Oliver syndrome
• molecular genetics
• Notch signaling
• Rho GTPase regulation
• vascular development

Article Highlights

• Adams–Oliver syndrome is a clinically and genetically heterogeneous disorder.

• Familial segregation supports both autosomal dominant and autosomal recessive inheritance, with sporadic cases representing around one-third.

• To date, six causal genes have been identified, accounting for 36% of reported AOS cases.

• Rho GTPase dysregulation and perturbed Notch signaling are central to disease development.

• The coexistence of cardiovascular features indicates disrupted vasculogenesis as the primary pathogenic mechanism, yet this remains to be fully explored.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Dr. Southgate was supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St. George’s, University of London.