ROBO4 – Aortic Valve Disease 3

Recent studies have robustly linked ROBO4 (HGNC:17985) to aortic valve disease 3 (MONDO_0032783) through a combination of genetic and functional evidence. Genetic analyses from multi‐patient studies have identified a diverse variant spectrum in ROBO4, including missense and truncating changes. One key study reported that rare ROBO4 variants segregated with disease in two families, supporting an autosomal dominant inheritance pattern (PMID:30455415). Additional data from case series demonstrated enrichment of rare deleterious variants in patients with early onset bicuspid aortic valve and thoracic aortic aneurysm (PMID:32748548).

The reported variant, for example, c.1900C>T (p.Arg634Cys), underscores the molecular heterogeneity observed in affected probands. Segregation analysis in these families further identified at least 2 additional affected relatives carrying the variant, reinforcing the genetic linkage. Such findings, coupled with observations of a diverse variant spectrum across multiple cohorts, enhance the clinical relevance of ROBO4 testing in patients with aortic valve disease 3.

Functional studies bolster these genetic findings. In vitro and in vivo assays have demonstrated that altered ROBO4 function results in impaired endothelial barrier function and reduced promoter activity, which are critical to vascular integrity (PMID:18519813). These mechanistic insights provide strong support for a pathogenic role of ROBO4 variants in the disease phenotype.

Notably, while one study did not observe significant enrichment of ROBO4 variants in certain thoracic aortic aneurysm cohorts (PMID:32748548), the overall weight of evidence from multiple independent research efforts supports a robust gene‑disease association.

The integration of observational genetic data with functional experimental findings yields a coherent narrative underlining the pathogenicity of ROBO4 variants. This body of work points to a clinically actionable target and provides valuable information for diagnostic decision‑making, commercial applications, and future publication efforts.

Key Take‑home: Screening for ROBO4 variants can significantly enhance early diagnosis and individualized management of aortic valve disease 3.

References

• Nature Genetics • 2019 • ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm PMID:30455415
• Molecular Genetics & Genomic Medicine • 2020 • Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 in early onset bicuspid aortic valve complications PMID:32748548
• Blood • 2008 • A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo PMID:18519813

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