BLOC1S5 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome (HPS) 11 in 2020 (Pennamen et al, PMID: 32565547). Hermansky-Pudlak syndrome 11 is a subtype of Hermansky-Pudlak syndrome, characterized by oculocutaneous albinism, bleeding diathesis, and platelet dysfunction. BLOC1S5 encodes subunit 5 of the Biogenesis of Lysome-related Organelles Complex 1, BLOC-1, which is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (PMID: 15102850). Variants in 4 of the 8 subunits of BLOC-1 have been associated with HPS in humans (Li et al., 2003, PMID: 12923531; Morgen et al., 2006 PMID: 16385460; Badolato et al., 2012, PMID: 22461475; Pennamen et al., 2020, PMID: 32565547). Evidence supporting this gene-disease relationship includes case-level and experimental data.
The mechanism of disease is expected to be biallelic loss of function.
Summary of Case Level Data (9.5 points): Four variants (Nonsense, frameshift, canonical splicing, and multi exon deletion) in this gene have been reported in 4 probands in 3 publications (PMID: 32565547, 34685610, 34058075). A variant in this gene segregated with disease in 1 additional family member (PMID: 34685610).
Summary of Experimental Data (4.25 points): This gene-disease association is supported by studies of protein interaction with other subunits of BLOC-1 (PMID: 12923531), mouse (muted) (PMID: 11912185) and zebrafish (PMID: 34058075) model systems that recapitulate the HPS phenotype, and rescue models in mouse melanocytes (PMID: 32565547).
In summary, BLOC1S5 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 11. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has held up over time.
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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