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.
"Tertiary analysis aimed at identifying candidate disease-causing variants was performed using CarpeNovo, a tertiary sequencing analysis software platform developed to support the Genomic Medicine Clinic and Program at Medical College of Wisconsin/Children’s Hospital of Wisconsin (MCW/CHW). This Java- and Oracle-based platform has been used at MCW/CHW to identify causative mutations in a variety of disorders (for example, see
[67,69]) and has undergone the rigorous testing and validation required for use in this clinical setting. Upward of 100 annotations were tagged to each of the WES-identified variants. "
[Show abstract][Hide abstract] ABSTRACT: Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS.
As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development.
Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent.
Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.
"Most reported recessive c10orf2 mutations are the result of homozygosity for the Y508C Finnish mutation . IOSCA however has also been reported in non-Finnish individuals due to other mutations including Y508C/A318T , Y508C/R29X , and T451I/T451I  (Figure 1). Whereas dominant mutations, causing progressive external ophthalmoplegia and mtDNA deletion tend to cluster in the linker region of the Twinkle protein, recessive mutations causing "
[Show abstract][Hide abstract] 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.
"Mutations in the MPV17 gene have been reported in patients who came to medical attention during infancy with liver failure, hypoglycemia, failure to thrive and neurological symptoms  . More recently, severe liver failure was found to be associated with autosomal recessive mutations in the TWINKLE gene, encoding the DNA helicase . "
[Show abstract][Hide abstract] 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.
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