AP3D1

Inheritance Pattern: AR

Disease ID:MONDO:0014885

Submitter: ClinGen

*AP3D1* was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 10 in 2016 (Ammann et al., PMID: 26744459). Hermansky-Pudlak syndrome 10 is a subtype of HPS, characterized by neutropenia, immune defects and neurological manifestations, in addition to oculocutaneous albinism and bleeding tendency. AP3D1 encodes the δ subunit of the adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). The AP3D1 deficiency phenotype presents a phenotypic spectrum that has overlap with that observed with AP3B1 and AP3B2 deficiencies (PMID: 27889060). Only 2 reports have been published so far, each reporting one homozygous deletion variant (PMIDs: 26744459, 30472485). In addition, a 12kb deletion in the mouse Ap3d gene is reported to be causative of a phenotype in the “mocha” mice, which is similar to HPS10 in humans (PMID: 9697856). Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 5.2 POINTS Variants in this gene have been reported in at least 2 probands in 2 publications (PMID: 26744459 , 30472485). As well as a third case reminiscent of HPS10, though milder and lacking the characteristic albinism (PMID: 36445457). The mechanism for disease is expected to be homozygous loss of function (PMID: 26744459). Summary of Experimental Data: 4.5 POINTS This gene-disease association is supported by studies in a spontaneously occurring mouse mutation, the “mocha” mice (PMID: 9697856) and a zebrafish model of syndromic albinism (PMID: 35816398). As well as an experimental rescue in patient cells (PMID: 26744459). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the HT GCEP on 02/26/2020. It was reevaluated on 04/03/2023. As a result of this reevaluation a new possible case (PMID: 36445457) and a new model organism (PMID: 35816398) were identified and the classification was increased from Limited to Moderate (SOP Version 9). It was again reevaluated on 09/03/2025 with no new evidence identified. Note from Primary Immune Regulatory Disorders GCEP added 01/05/2026: The immunodeficiency/immune dysregulation phenotype in HPS10 is associated with absent NK cell degranulation and impaired T cell degranulation (PMID: 30472485). Patients can have hepatosplenomegaly and recurrent fevers, but other biochemical criteria (ferritin, fibrinogen, triglycerides, sIL2R) for hemophagocytic lymphohistiocytosis are not met (PMID: 30472485). The B cell compartment is mostly intact, and T cell counts can be quantitatively altered during infection episodes (PMID: 30472485). The infection susceptibility is related to neutrophil defects but also due to defects in cellular cytotoxicity (PMID: 30472485, 36445457, 9697856). The latter citation supports the mechanistic basis of vesicle trafficking defects in AP3D1, which underlie immune dysfunction.

Inheritance Pattern: Unknown

Disease ID:MONDO:0014885

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014885

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014885

Submitter: PanelApp Australia