Submission Details

The RAB27A gene is located on chromosome 15 at 15q21.3 and encodes the RAB27A protein, which is a member of the family of small GTPases involved in vesicular fusion and trafficking. The RAB27A gene was first reported in relation to autosomal recessive Griscelli syndrome in 2000 (Pastural et al., PMID: 10704277). Biallelic variants in RAB27A (including nonsense, frameshift, splice, and missense variants) were subsequently identified in 16 patients with Griscelli syndrome by Menasche et al., 2000 (PMID: 10835631). The patients exhibited various degrees of skin hypopigmentation and a silvery-gray sheen of the hair with large pigment aggregates in hair shafts. In all of these patients, at least 1 episode of hemophagocytic syndrome had occurred, characterized by acute onset of uncontrolled lymphocyte and macrophage activation, resulting in infiltration and hemophagocytosis in multiple organs. This form is referred to as Griscelli syndrome, type 2 (MIM: 607624). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least fifteen probands in ten publications (Schuster et al., 2011 PMID: 11571516; Arico et al., 2002 PMID 12098069; Sanal et al., 2002 PMID: 12148598; Anikster et al., 2002 PMID: 12058346; Aksu et al., 2003 PMID: 12525785; Sheela et al., 2004 PMID 15475639; Bizario et al., 2004 PMID: 15163896; Meschede et al., 2008 PMID: 19030707). The gene-disease relationship is supported experimental evidence including a mouse model, which show pigmentary dilution of coat color and abnormal distribution of melanosome in ashen mice (Wilson et al., 2000 PMID: 10859366), and the inability of cytotoxic T lymphocytes from ashen mice to kill target cells or to secrete granzyme A and hexosaminidase (Stinchcombe et al., 2001 PMID: 11266472). In summary, the RAB27A gene is definitely associated with Griscelli syndrome, type 2 (autosomal recessive inheritance). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Due to the overlapping phenotype of Griscelli Syndrome type 2 (GS2) with immunodeficiency and immune dysregulation, the PIRD GCEP has provided an addendum to this gene curation.

Patients with GS2 can have normal NK cell phenotyping with aberrant NK cell cytotoxicity, CD107a degranulation and antibody-dependent cellular cytotoxicity (ADCC). There can be phenotypic heterogeneity in GS2, even with a single pathogenic RAB27A variant, with severely affected and asymptomatic patients. Also, heterozygous RAB27A variants (c.259G>C) have been reported to develop HLH features and demonstrated decreased NK cell cytotoxicity, granule polarization and degranulation but had normal immune synapse formation, suggesting there is a partial dominant-negative effect with this variant. Further, a novel structural variant at the 5'UTR of RAB27A causes an atypical form of GS2 with late-onset HLH, including neuroinflammation, skin granulomas, lymphoma but normal pigmentation. A different novel RAB27A variant (c.551G>A) resulted in late-onset HLH with EBV-driven lymphoproliferation. This variant also results in normal pigmentation and demonstrated variability in effector protein binding with strong binding to MUNC13-4 and attenuated binding to SLP2A with impaired lymphocyte exocytosis.

PMIDs: 26880764; 29522846; https://doi.org/10.1002/ajmg.a.61829; DOI: 10.1007/s10875-022-01315-4