Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53221, USA.
Journal of pediatric gastroenterology and nutrition (Impact Factor: 2.87). 06/2011; 54(2):291-4. DOI: 10.1097/MPG.0b013e318227e53c
Source: PubMed

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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