Griscelli Syndrome-Type 2 (GS2) via the RAB27A Gene

Griscelli syndrome (GS) is classified into three different subtypes, GS1 (OMIM 214450), GS2 (OMIM 607624), and GS3 (OMIM 609227), all of which are characterized by partial albinism, i.e. pigmentary dilution of the skin and hair. Patients with GS typically have large clumps of pigment irregularly distributed along hair shafts giving a silvery-gray appearance to hair color. GS1 is associated with severe primary neurologic defects while GS2 is associated with hemophagocytic lymphohistiocytosis (HLH / FHL) (see OMIM 267700). HLH is characterized by excessive, uncontrolled activation, and proliferation of T cells and macrophages that infiltrate tissues and cause organ failure. Common symptoms of HLH include: fever, hepatosplenomegaly, pancytopenia, attenuated or absent NK cell function, and hemophagocytosis (Henter et al. Pediatr Blood Cancer 48:124-131, 2007). Griscelli syndrome type 3 (GS3) is characterized by pigmentary dilution only. GS is commonly diagnosed between the ages of 4 months and 7 years.

GS is an autosomal recessive disorder caused by variants in MYO5 (GS1), RAB27A (GS2), or MLPH (GS3). Variants in these genes affect melanosome trafficking and with GS1 and GS2, affect additional vesicular transport events. For example, RAB27A encodes a small GTPase (Rab27a) that is required for both anchoring melanosomes in melanocytes and for cytolytic granule secretion in T cells and NK cells (reviewed in Van Gele et al. Pigment Cell Melanoma Res 22:268-282, 2009). Thus, GS2 patients develop HLH and partial albinism. To date, about 30 causative variants in RAB27A have been identified, comprising missense variants, small and large deletions, and splice site variants (Meschede et al. Braz J Med Biol Res 41:839-848, 2008). Some missense variants have been shown to affect the Rab27a GTP-binding motif and protein-protein interaction domains (Menasche et al. Blood 101:2736-2742, 2003). Variants in RAB27A do not affect T cell or NK cell numbers but rather inhibit granule exocytosis in these cells similar to HLH / FHL genes. Rarely, variants in RAB27A result in immunological deficiencies without hemophagocytosis (Aksu et al. Am J Med Genet A 116A:329-333, 2003).

Sensitivity of this test is currently unknown.

This test provides full coverage of all coding exons of the RAB27A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).