Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure.
ABSTRACT In severe liver failure, the treatment of choice is liver transplantation. However, in a proportion of these patients, transplantation has been shown to be futile. Conversely, specific disorders may show improvement, or respond to specific treatment. In either situation, a molecular diagnosis can prevent a child from undergoing an inappropriate and expensive procedure.In many disorders, overlapping clinical phenotypes and locus heterogeneity can significantly hamper establishing a diagnosis, next generation sequencing may allow for more comprehensive establishment of etiology, allowing for focused management. In this report we demonstrate the utility of such an approach.Our case presented in infancy with acute liver failure; routine etiological screening was negative. Liver biopsy showed active cirrhosis with bile ductular proliferation and scattered macrovesicular steatosis. mtDNA content in the liver was decreased but no mutations in, the known genes POLG, MPV17, or DGUOK were detected.She was enrolled in a research study for genomic sequencing. Only two significant variants were detected, both in C10Orf2 (TWINKLE), a novel truncating mutation c.85C > T (p.R29X) and the previously described c.1523A > G (p.Y508C). Dominant mutations in this gene have been shown to cause progressive external opthalmoplegia and recessive mutations with infantile onset spinocerebellar ataxia with two cases developing liver disease. Thus, we defined a new presentation of Twinkle associated disease.More significantly, given the features and molecularly confirmed mtDNA depletion we were able to confidently counsel the parents, and a decision was made that she would not be an appropriate candidate for liver transplantation.
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ABSTRACT: This work reviews the most relevant present-day processing methods used to improve the accuracy of multimodal nonlinear images in the detection of epithelial cancer and the supporting stroma. Special emphasis has been placed on methods of non linear optical (NLO) microscopy image processing such as: second harmonic to autofluorescence ageing index of dermis (SAAID), tumor-associated collagen signatures (TACS), fast Fourier transform (FFT) analysis, and gray level co-occurrence matrix (GLCM)-based methods. These strategies are presented as a set of potential valuable diagnostic tools for early cancer detection. It may be proposed that the combination of NLO microscopy and informatics based image analysis approaches described in this review (all carried out on free software) may represent a powerful tool to investigate collagen organization and remodeling of extracellular matrix in carcinogenesis processes.Cancer informatics 01/2014; 13:67-76. DOI:10.4137/CIN.S12419
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ABSTRACT: The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, preprocessing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics.Cancer informatics 09/2014; Cancer Informatics 2014(Suppl. 2):67-82. DOI:10.4137/CIN.S13779
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ABSTRACT: Severe congenital hypertriglyceridemia is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week old Hispanic female with severe hypertriglyceridemia (12,031 mg/dl; normal limit 150 mg/dl) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole exome-sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated hypertriglyceridemia, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.Journal of pediatric gastroenterology and nutrition 03/2014; 59(1). DOI:10.1097/MPG.0000000000000363 · 2.18 Impact Factor