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A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis
Author(s) -
Grandin Virginie,
Sepulveda Fernando E,
Lambert Nathalie,
Al Zahrani Mofareh,
Al Idrissi Eman,
AlMousa Hamoud,
Almanjomi Fahd,
AlGhonaium Abdulaziz,
K. Habazi Murad,
A. Alghamdi Hamza,
Picard Capucine,
BoleFeysot Christine,
Nitschke Patrick,
Ménasché Gaël,
Saint Basile Geneviève
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23274
Subject(s) - biology , genetics , gene duplication , breakpoint , point mutation , exon , indel , frameshift mutation , indel mutation , mutation , gene , genotype , chromosomal translocation , single nucleotide polymorphism
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.