RAB23 – Carpenter Syndrome

Carpenter syndrome is a multiple congenital malformation disorder characterized primarily by craniosynostosis and obesity, with frequent findings of polysyndactyly and additional skeletal anomalies. This phenotype is consistently reported across several independent studies supporting its clinical recognition (PMID:23599695).

Multiple case reports and multi‐patient studies have documented autosomal recessive inheritance of Carpenter syndrome due to mutations in RAB23. Reports include families with homozygous truncating and splice site mutations, establishing both the phenotypic spectrum and the segregation of the defect in affected relatives (PMID:25168863).

Genetic evidence highlights a variety of pathogenic changes in RAB23, including nonsense, frameshift, and splice mutations. In one notable study, a consanguineous Emirati family was shown to carry a homozygous splice site mutation leading to a cryptic acceptor site activation and an eight nucleotide deletion; such consistent findings across independent cohorts bolster the diagnostic confidence (PMID:23599695).

A representative variant—c.482-1G>A (p.Val161fsTer3)—exemplifies the molecular basis for the disease. This variant, found in multiple independent reports, results in a frameshift and premature truncation of the RAB23 protein, thereby disrupting its prenylation and subsequent membrane targeting. Additional reports describe similar loss-of-function variants, underscoring the genetic heterogeneity yet mechanistic convergence within Carpenter syndrome (PMID:21412941).

Functional studies further support a pathogenic role for RAB23 mutations by demonstrating defective prenylation and altered Hedgehog signaling. These cellular and biochemical assays, including animal model studies, consistently show that loss-of-function mutations in RAB23 impair its normal function, providing a molecular explanation for the cranial and limb anomalies observed clinically (PMID:17503333; PMID:23063620).

In summary, the robust genetic and functional evidence firmly links pathogenic RAB23 variants with Carpenter syndrome. For diagnostic decision-making, routine molecular testing of RAB23 is recommended in patients with the characteristic craniosynostosis and dysmorphic features. This information supports clinical utility, fosters commercial development of diagnostic assays, and provides a reliable basis for future publication.

References

• Molecular syndromology • 2013 • A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family PMID:23599695
• American journal of medical genetics. Part A • 2014 • Prenatal findings in Carpenter syndrome and a novel mutation in RAB23 PMID:25168863
• Human mutation • 2011 • Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay PMID:21412941
• American journal of human genetics • 2007 • RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial‑suture development and obesity PMID:17503333
• American journal of human genetics • 2012 • Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization PMID:23063620

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