Bardet-Biedl syndrome (BBS) is a heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, hypogenitalism, and an increased incidence of diabetes and hypertension. No information is available regarding the specific function of BBS2. We show that mice lacking Bbs2 gene expression have major components of the human phenotype, including obesity and retinopathy. In addition, these mice have phenotypes associated with cilia dysfunction, including retinopathy, renal cysts, male infertility, and a deficit in olfaction. With the exception of male infertility, these phenotypes are not caused by a complete absence of cilia. We demonstrate that BBS2 retinopathy involves normal retina development followed by apoptotic death of photoreceptors, the primary ciliated cells of the retina. Photoreceptor cell death is preceded by mislocalization of rhodopsin, indicating a defect in transport. We also demonstrate that Bbs2 ؊/؊ mice and a second BBS mouse model, Bbs4 ؊/؊ , have a defect in social function. The evaluation of Bbs2 ؊/؊ mice indicates additional phenotypes that should be evaluated in human patients, including deficits in social interaction and infertility.Bardet-Biedl syndrome ͉ mouse model ͉ obesity
Purpose To devise a comprehensive multi-platform genetic testing strategy for inherited retinal disease and describe its performance in 1,000 consecutive families seen by a single clinician. Methods The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to one of 62 diagnostic categories and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from two (a multiplex allele-specific assay for the most common mutations in BBS1 and BBS10) to nearly 900,000 (the coding sequences, and splice junctions of 305 genes known to cause inherited retinal disease). Results Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 70% of these 104 genes have coding sequences small enough to be efficiently packaged into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families) while mutations in 80 genes caused disease in five or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole exome sequencing of the remaining 424 families revealed mutations in an additional 182, and whole genome sequencing of four of the remaining 242 families revealed two additional genotypes that were invisible by the other methods. Performing the testing in a clinically-focused tiered fashion would be 6.1% more sensitive, 17.7% less expensive and have a significantly lower average false genotype rate than using whole exome sequencing to assess more than 300 genes in all patients (7.1 vs. 128%; p<0.001). Conclusions Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically-directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost.
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