Novel 47.5-kb deletion in RAB27A results in severe Griscelli Syndrome Type 2

Abstract

Griscelli syndrome (GS), a rare autosomal recessive disorder characterized by partial albinism and immunological impairment and/or severe neurological impairment, results from mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes. We identified a Hispanic patient born of a consanguineous union who presented with immunodeficiency, partial albinism, hepatic dysfunction, hemophagocytosis, neurological impairment, nystagmus, and silvery hair indicative of Griscelli Syndrome Type 2 (GS2). We screened for point mutations, but only exons 2-6 of the patient's DNA could be PCR-amplified. Whole genome analysis using the Illumina 1M-Duo DNA Analysis BeadChip identified a homozygous deletion in the patient's DNA. The exact breakpoints of the 47.5-kb deletion were identified as chr15q15-q21.1: g.53332432_53379990del (NCBI Build 37.1); the patient lacks the promoter and 5'UTR regions of RAB27A, thus confirming the diagnosis of GS2.

Fig. 1

Clinical information of patient with Griscelli Type 2 Syndrome. (A) The pedigree of the proband’s (P) family shows consanguinity arising from a marriage of second cousins. (p = pregnancy; n = multiple siblings, number unknown) (B) The silvery hair of the patient with GS2 shows characteristic pigment clumping (right) compared to a hair of an unaffected dark haired person (left). Sizebar, 50 µm.

Fig. 2

Experimental and schematic representations of homozygous deletion in Rab27A gene of patient with Griscelli Type 2 Syndrome. (A) Illumina® 1M-Duo DNA Analysis BeadChip results illustrating a large scale deletion. (B) Schematic basis of 47.5-kb deletion relative to the most abundant transcript of the Rab27A gene (GenBank NM_004580). The deletion (shaded gray line) removes the first exon, which is non-coding. The deletion does not contain any coding sequence. Cross-hatched boxes indicate 5’-UTR of the transcript and the checkered box indicates 3’-UTR of all transcripts. Black boxes indicate coding region of Rab27A. (C) Two primers (block arrows) were used to amplify across the deletion that occurs within the 9-bp stretch shared by the two regions. (D) Sequence analysis of the breakpoint region. Diagrams are not to scale.