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: Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.08/2012; 2012:303096. DOI:10.1155/2012/303096
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ABSTRACT: This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½ months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma.Molecular Genetics and Metabolism 11/2011; 105(2):228-36. DOI:10.1016/j.ymgme.2011.11.006 · 2.83 Impact Factor
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ABSTRACT: Abstract In the relatively short time frame since the introduction of next generation sequencing, it has become a method of choice for complex genomic research studies. As a paradigm shifting technology, we are now witnessing its translation into clinical diagnostic laboratories for patient care. Multi-gene panels for a variety of disorders are now available in several clinical laboratories based on targeted gene enrichment followed by next generation sequencing. Genome wide interrogation of protein coding regions, or exome sequencing, has been successfully and increasingly applied in the research setting for the elucidation of candidate genes and causal variants in individuals and families with a diversity of rare and complex genetic disorders. Based on this progress, exome sequencing is also beginning a translational process into clinical practice. However, introducing exome sequencing as a diagnostic modality poses new technical and bioinformatics challenges for clinical laboratories. In this review, we present technical and bioinformatics aspects of exome sequencing, describe representative examples from the literature of how exome sequencing has been used for candidate gene discovery, and discuss considerations for its clinical translation.Clinical Chemistry and Laboratory Medicine 01/2011; 50(7):1161-8. DOI:10.1515/cclm-2011-0841 · 2.96 Impact Factor