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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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