ATP6V1B2 – Autosomal Dominant Deafness-Onychodystrophy Syndrome

ATP6V1B2 encodes the B2 subunit of the vacuolar H⁺-ATPase and is causally linked to autosomal dominant deafness-onychodystrophy (DDOD) syndrome. The condition is characterized by congenital sensorineural hearing loss and nail dystrophy, often with variable digital anomalies.

1. Clinical Validity

Multiple independent studies support a Strong gene–disease association. A recurrent heterozygous truncating variant, NM_001693.4:c.1516C>T (p.Arg506Ter), was identified in nine affected individuals from eight unrelated families with DDOD syndrome (PMID:32873933). This variant is absent from population databases and segregates with disease status, consistent with a haploinsufficiency mechanism corroborated by functional models.

2. Genetic Evidence

Inheritance is autosomal dominant. The primary evidence comprises nine probands harboring the same truncating c.1516C>T (p.Arg506Ter) variant across eight families (PMID:32873933). No additional segregating relatives beyond the index cases have been reported. Population data show absence of loss-of-function variants in controls, and the variant has been recurrently observed de novo, meeting ClinGen criteria for strong genetic evidence.

3. Functional and Experimental Evidence

Patient-derived iPSCs carrying the c.1516C>T variant were corrected via CRISPR/Cas9, restoring normal pluripotency and tri-lineage differentiation potential (PMID:33714068). A heterozygous Atp6v1b2emR506* mouse model exhibits phenotypes overlapping human neuropathology, including hyperactivity and reduced seizure threshold, supporting a dominant-negative or haploinsufficiency mechanism (PMID:37628590).

4. Integration and Conclusion

Collectively, the replication of a recurrent truncating variant in multiple unrelated DDOD cases, its absence in controls, and concordant functional data establish a Strong ClinGen classification for ATP6V1B2–DDOD association. While further segregation data would strengthen family-based evidence, current genetic and experimental findings are sufficient for clinical diagnostic decision-making.

Key Take-home: Heterozygous truncating variants in ATP6V1B2, notably c.1516C>T (p.Arg506Ter), are a validated cause of autosomal dominant deafness-onychodystrophy syndrome and should be included in targeted genetic testing panels.

References

• Genetics in Medicine • 2021 • DOORS syndrome and a recurrent truncating ATP6V1B2 variant PMID:32873933
• Human Genetics • 2022 • Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes. PMID:34232384
• Stem Cell Research • 2021 • Generation of a gene corrected human isogenic iPSC line (CPGHi002-A-1) from a DDOD patient with heterozygous c.1516 C>T mutation in the ATP6V1B2 gene. PMID:33714068
• Genes • 2023 • The ATP6V1B2 DDOD/DOORS-Associated p.Arg506 Variant Causes Hyperactivity and Seizures in Mice.* PMID:37628590

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