ATP6V1B2 – DOORS Syndrome

ATP6V1B2 has been robustly associated with DOORS syndrome, a multisystem disorder characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Multiple lines of evidence from both case reports and multi‐patient studies support this association, with several independent studies reporting a recurrent truncating variant. In one key multi‐patient study, the recurrent variant c.1516C>T (p.Arg506Ter) was identified in nine probands from eight unrelated families (PMID:32873933). This observation, combined with additional case reports and supportive neuropathological findings (PMID:32849222), underscores the strength of the genetic evidence.

Genetic studies consistently demonstrate an autosomal dominant inheritance pattern in DOORS syndrome patients harboring ATP6V1B2 variants. Although formal segregation data from affected relatives is limited, the recurrence of the truncating variant across unrelated families provides strong indirect segregation evidence. Aside from the truncating allele, a spectrum of other variant classes has been reported, further consolidating the gene‐disease association. This is critical for diagnostic decision‑making, as it highlights ATP6V1B2 as a reliable marker in clinical molecular testing.

Functional assessments have shown that ATP6V1B2 mutations disrupt lysosomal acidification and autophagic flux, processes that are fundamental to cellular homeostasis. Experimental evidence from cellular assays and animal models replicates key aspects of the DOORS syndrome phenotype, linking the molecular defect to clinical features such as seizures and neurodevelopmental delay (PMID:37628590). These functional studies reinforce the genetic findings and provide a mechanistic basis for the disease, which is essential for both research and potential therapeutic targeting.

While ATP6V1B2 mutations have also been implicated in overlapping syndromes such as dominant deafness-onychodystrophy, the convergence of multiple case reports and detailed functional studies specifically supports its role in DOORS syndrome. Conflicting evidence is minimal, and the overall data converges on a strong causal role for ATP6V1B2 in the pathogenesis of the syndrome. This integrated genomic and experimental evidence provides a compelling narrative for clinical use.

The accumulated evidence extends beyond basic clinical correlation, offering detailed insights into pathogenic mechanisms that deepen our understanding of DOORS syndrome. The recurrent detection of the truncating variant, alongside consistent functional disruption, exceeds the conventional ClinGen scoring maximum, reinforcing the clinical utility of ATP6V1B2 testing. Moreover, the data supports its incorporation into diagnostic algorithms to better predict phenotypic outcomes.

Key Take‑home sentence: ATP6V1B2 variants, particularly the recurrent c.1516C>T (p.Arg506Ter), represent a robust and clinically actionable marker for DOORS syndrome, integrating strong genetic and functional evidence for diagnostic and therapeutic development.

References

• Frontiers in Neurology • 2020 • Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene PMID:32849222
• Genetics in Medicine • 2021 • DOORS Syndrome and a Recurrent Truncating ATP6V1B2 Variant PMID:32873933
• Genes • 2023 • The ATP6V1B2 DDOD/DOORS-Associated p.Arg506 Variant Causes Hyperactivity and Seizures in Mice* PMID:37628590
• HGG Advances • 2024 • Dominantly Acting Variants in ATP6V1B2 Cause a Multisystem Phenotypic Spectrum PMID:39210597

Evidence Based Scoring (AI generated)