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

International audienceGriscelli 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

Testutrustning för böjning av massiva ämnen av bok och björk

Upprättat; 2007; 20141022 (dicsan

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Background: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. Methods: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. Results: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). Conclusion: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data

Additional file 4: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S4. (A) The number of patients with isolated or combined infections, and (B) the number of patients with isolated or combined immunophenotypes, and the percentage for which we have reported a genetic diagnosis. (XLSX 11 kb

Additional file 3: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S3. Variants of unknown significance (class 3) and variants in TRAF3 identified in 17 patients suffering from primary immunodeficiencies. (XLSX 11 kb

Additional file 2: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S2. Shows all causative mutations identified in 72 patients from 68 families suffering from primary immunodeficiencies. (XLSX 17 kb

Additional file 5: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S5. Quality information of the WES technology, with the mean target coverage, and the % of bases with >â 20Ă coverage. (XLSX 22 kb

Additional file 1: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S1. Overview of all clinical characteristics of the patients included in our diagnostic PID cohort, including all immunophenotype characteristics. (XLSX 63 kb

Additional file 6: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S6. Information on all large >â 5-Mb homozygous regions per patient, detected in the exome. Of each region, the genomic location, size, % homozygous variants, and the detected mutation are provided. (XLSX 158 kb