A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis

Abstract

Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

“…We report the first large-scale deletion of IL12RB1 (dup10-12). CNVs are not easy to detect by routine Sanger sequencing [42, 50, 60, 61]. In this study, a simple comparison of the read-depth data obtained for targeted high-throughput sequencing unmasked five CNVs that were then delimited more precisely by Sanger sequencing.…”

“…Sequences were aligned with the hg19 reference human genome with Burrows-Wheeler Aligner version 0.6.2.13 [41]. CNVs were analyzed as previously described [42, 43]. The Sanger sequencing of IL12RB1 exons and their flanking regions was performed as previously described [36].…”

Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds

“…Sequences were aligned with the GRCh37hg19 human genome with Burrows-Wheeler Aligner version 0.6.2.13 [ 18 ]. Copy number variations (CNVs) were analyzed as previously described [ 19 ]. For precise analyses of breakpoint, regions were analyzed for the presence of repetitive elements using the RepeatMasker track ( http://www.repeatmasker.org/ ) in the UCSC genome browser ( https://genome.ucsc.edu/ ) [ 20 ].…”

Congenital Hypopigmentary Disorders with Multiorgan Impairment: A Case Report and an Overview on Gray Hair Syndromes

“…Based on the dermatological characteristics, congenital pigmentary disorders have been classified in gray hair syndromes (GHSs), localized hypopigmentary hair and skin defect syndromes (Waardenburg syndrome and Piebaldism) and generalized hypopigmentary hair and skin defect syndromes (Oculocutaneous Albinism and Tietz syndrome) [1,2,3,4,5,6,7,8,9].…”

“…Although GHSs are extremely heterogeneous diseases, they are all clinically hallmarked by inborn silvery gray hairs [5]. Table 1 summarizes the clinical and genetic characteristics of all known GHSs to date [1,2,3,4,5,6,7,8,9,10].…”