AP3D1 – Hermansky-Pudlak Syndrome 10

The association between AP3D1 (HGNC:568) and Hermansky-Pudlak Syndrome 10 (MONDO_0014885) is supported by robust clinical evidence. Multiple affected individuals in a consanguineous family exhibited sensorineural hearing loss and premature ovarian insufficiency, with the homozygous missense variant segregating with the phenotype. This evidence attains a ClinGen category of Strong given the clear segregation pattern and the convergence of clinical and molecular findings (PMID:36445457).

The genetic evidence indicates an autosomal recessive mode of inheritance. In the reported family, detailed case assessments revealed that the homozygous variant, c.2131G>A (p.Val711Ile), was observed in several affected individuals including siblings and a single affected female with ovarian failure. In addition to the primary proband, at least three additional affected relatives were confirmed to carry this variant, reinforcing the variant’s role in pathogenesis (PMID:36445457).

The missense variant c.2131G>A (p.Val711Ile) alters the AP3D1 protein sequence and is predicted to disrupt key protein–protein interactions critical for inner ear function. Notably, heterozygous carriers in the family exhibited milder sensorineural hearing loss, suggesting a dosage effect that aligns with the observed semi‐dominant features in auditory phenotypes. This variant was consistently identified in molecular screening and validated by Sanger sequencing in the proband and affected relatives (PMID:36445457).

Functional studies have demonstrated that the AP3D1 missense variant adversely affects the formation and stability of the AP3 complex. Protein modeling analyses indicate that the p.Val711Ile change interferes with normal protein–protein interactions, which is critical for lysosome-related organelle function. These in vitro assessments and rescue experiments provide moderate experimental support for the pathogenic mechanism underlying the hearing loss and associated features noted in Hermansky-Pudlak Syndrome 10 (PMID:36445457).

While classical Hermansky-Pudlak Syndrome typically includes features such as oculocutaneous albinism, the presenting family exhibited a milder phenotype that lacks this hallmark, thereby expanding the phenotypic spectrum of AP3D1-associated disease. This discrepancy underscores the importance of considering both typical and atypical manifestations when evaluating patients with suspected HPS10, and it suggests that additional modifying factors may influence expressivity (PMID:36445457).

In conclusion, the convergence of genetic segregation, detailed phenotypic evaluation, and corroborative functional data establishes a strong association between AP3D1 and Hermansky-Pudlak Syndrome 10. This comprehensive evidence supports the use of AP3D1 genetic testing for diagnostic decision-making and informs both clinical management and future research priorities.

References

• Human Genetics • 2023 • A homozygous AP3D1 missense variant in patients with sensorineural hearing loss as the leading manifestation PMID:36445457

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