Together with previous studies from our group, the present study demonstrates that the effects of WBV on joint tissues vary in a strain-specific manner. These findings highlight the need to examine genetic or physiological differences that may underlie susceptibility to the deleterious effects of WBV on joint tissues.
Leber congenital amaurosis (LCA) is a severe disease that leads to complete blindness in children, typically before the first year of life. Due to the clinical and genetic heterogeneity among LCA and other retinal diseases, providing patients with a molecular diagnosis is essential to assigning an accurate clinical diagnosis. Using our gene panel that targets 300 genes that are known to cause retinal disease, including 24 genes reported to cause LCA, we sequenced 43 unrelated probands with Brazilian ancestry. We identified 42 unique variants and were able to assign a molecular diagnosis to 30/43 (70%) Brazilian patients. Among these, 30 patients were initially diagnosed with LCA or a form of early-onset retinal dystrophy, 17 patients harbored mutations in LCA-associated genes, while 13 patients had mutations in genes that were reported to cause other diseases involving the retina.
The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS's) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis we validated 23 VUS's as splicing variants that likely explain disease in 26 patients. Using our results we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines.
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