BackgroundPathogenicity predictors are integral to genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically relevant dataset has not been undertaken.MethodsWe derive two validation datasets: an ‘open’ dataset containing variants extracted from publicly available databases, similar to those commonly applied in previous benchmarking exercises, and a ‘clinically representative’ dataset containing variants identified through research/diagnostic exome and panel sequencing. Using these datasets, we evaluate the performance of three recent meta-predictors, REVEL, GAVIN and ClinPred, and compare their performance against two commonly used in silico tools, SIFT and PolyPhen-2.ResultsAlthough the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically representative dataset. Using our clinically relevant dataset, REVEL performed best with an area under the receiver operating characteristic curve of 0.82. Using a concordance-based approach based on a consensus of multiple tools reduces the performance due to both discordance between tools and false concordance where tools make common misclassification. Analysis of tool feature usage may give an insight into the tool performance and misclassification.ConclusionOur results support the adoption of meta-predictors over traditional in silico tools, but do not support a consensus-based approach as in current practice.
We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.
Objective. Osteoarthritis (OA) is a complex heterogeneous joint disease affecting more than 35 million people worldwide. The current gold standard diagnostic investigation is the plain radiograph, which lacks sensitivity. Biochemical markers have the potential to act as adjunct markers for imaging in the assessment of knee OA. We undertook this study to determine the association between individual biochemical markers and radiographic features, and to establish whether the association is strengthened when selected biochemical markers are combined into a single factor (a theoretical marker).Methods. Twenty serum and urinary biochemical markers were analyzed in 119 patients with predominantly tibiofemoral knee OA. Pearson's correlation was performed, and corresponding coefficients of determination (R 2 ) were calculated to determine the association between biochemical markers and a range of imaging features from radiographs and dual x-ray absorptiometry of the knee. Biochemical markers demonstrating a significant association (P < 0.05) with a specific imaging feature were combined by principal components analysis (PCA). Pearson's correlation was repeated to establish whether the combined panel of biochemical markers showed a stronger association with imaging than the best single marker.Results. Fourteen biochemical markers showed significant associations with one or more imaging features. By combining specific panels of biochemical markers to form factors, the association of markers with imaging features (R 2 ) increased from 11.9% to 22.7% for the Kellgren/Lawrence (K/L) score, from 5.9% to 9.2% for joint space width (JSW), from 6.6% to 10.8% for sclerosis, from 13.5% to 22.6% for osteophytes, and from 12.0% to 14.2% for bone mineral density (BMD). Biochemical markers identifying patients with osteophytes overlapped with those correlated with a high K/L score, while markers of subchondral BMD formed a completely separate group. Biochemical markers of JSW included markers associated with both osteophytes and BMD.Conclusion. The PCA results suggest that biochemical marker combinations may be more sensitive than individual biochemical markers for reflecting structural damage in patients with knee OA. The differences in biochemical marker profiles associated with osteophytes compared with those associated with subchondral BMD raise the possibility that these 2 processes, commonly seen in bone in knee OA, have underlying biologic differences.Osteoarthritis (OA) is a complex heterogeneous joint disease with a prevalence of 18% in persons age Ͼ55 years in the UK (1). With ϳ35 million people affected worldwide, OA is a major cause of pain and disability, and its incidence is increasing as life expectancy continues to rise (2). The current gold standard for diagnosing OA is the plain radiograph, which has many methodologic shortcomings, and, in spite of efforts to improve techniques (3,4), inaccuracies may occur from subtly different views of the image, degree of flexion, intra-and interobserver discrepancies, and "anticip...
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
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