Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

Taylor, Robert W.; Pyle, Angela; Griffin, Helen; Blakely, Emma L.; Duff, Jennifer; He, Langping; Smertenko, Tania; Alston, Charlotte L.; Neeve, Vivienne C.M.; Best, Andrew; Yarham, John W.; Kirschner, Janbernd; Schara, Ulrike; Talim, Beril; Topaloǧlu, Haluk; Barić, Ivo; Holinski‐Feder, Elke; Schöser, Benedikt; Czermin, Birgit; Kleinle, Stephanie; Morris, Andrew A. M.; Vassallo, Grace; Gorman, Gráinne; Ramesh, Venkateswaran; Turnbull, Doug M.; Santibanez‐Koref, Mauro; McFarland, Robert; Horvath, Rita; Chinnery, Patrick F.

doi:10.1001/jama.2014.7184

Cited by 326 publications

(326 citation statements)

References 38 publications

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“…To date, 26 patients are reported with LTBL (12 by Steenweg et al (2012), one by Talim et al (2013), two by Taylor et al (2014), one by Biancheri et al (2015), one by Kohda et al (2016), one by Kevelam et al (2016), one by Danhauser et al (2016), one by Taskin et al (2016), one by G€ ung€ or et al (2016), two by Şahin et al (2016) and two by Pronicka et al (2016)), with our patient being the 26th reported patient. The phenotype of our patient fits the severe group of LTBL patients, mostly due to signs of perinatal presentation of the disease and rapid decline of her clinical status.…”

Section: Discussionmentioning

confidence: 61%

“…Although liver respiratory chain activity was normal, there was evident liver dysfunction. Liver involvement was also described in six additional EARS2 patients, which included one or more of neonatal transient icterus, hepatomegaly, fatty liver and steatosis (Steenweg et al 2012;Talim et al 2013;Taylor et al 2014;Pronicka et al 2016). Post-mortem examination of the liver from the patient reported by Talim et al (2013) also found COXdeficiency.…”

Section: Discussionmentioning

confidence: 87%

“…Unfortunately none of these reports had brain MR reports and images available for comparison, except for corpus callosum dysgenesis and agenesis, described for each patient on brain MR and brain sonogram, respectively. The two patients reported by Taylor et al (2014) (patients 16 and 17) also had a fatal outcome with a severe neurometabolic disorder, with neonatal or very early onset presentation of LTBL.…”

Section: Discussionmentioning

confidence: 97%

“…Polyphen 2, SIFT and Align GVGD were used to predict effect on protein function. Identified recessive variants were validated and segregation studies were performed by Sanger sequencing (Taylor et al 2014). …”

Section: Whole Exome Sequencing and Analysismentioning

confidence: 99%

“…These disorders often manifest during childhood with typically multi-organ phenotypes. A genotype-phenotype correlation has been ascertained for several mt-aaRS genes with some tissue specificity, probably due to cell-type specific differences in response to mutations Biancheri et al 2015;Taylor et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

et al. 2016

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Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Section: Whole Exome Sequencing and Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

et al. 2016

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Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy

Sommerville

Alston

et al. 2017

JAMA Neurol

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IMPORTANCE YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. OBJECTIVES To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. DESIGN, SETTING, AND PARTICIPANTS An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants

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The Effect of Neurological Genomics and Personalized Mitochondrial Medicine

Horvath

Chinnery

2017

JAMA Neurol

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Genetic diagnostics have undergone a revolution in the last decade, fueled by technological advances heralded by the development of massively parallel DNA sequencing. Within a remarkably short time, the new chemistry moved from the research laboratory into clinical practice, accelerating the pace of gene discovery and allowing the rapid diagnosis of genetic disorders on an unprecedented scale. There is a strong argument that so-called next or third generation sequencing will have the greatest effect in neurology, which is characterized by a seemingly endless list of discrete clinical syndromes, many thought to have a unique genetic basis. Until 2011, clinical neurogenetic practice has been frustrating. It has been difficult to screen more than a handful of the known genetic causes of a particular disorder, but we now face the real prospect of a reaching genetic diagnosis for every patient walking to the clinical door. Mitochondrial disorders provide a good illustration of the effect of this new technology in neurogenetic practice.Mitochondrial disorders are the bane of the generalist. The myriad of clinical features overlap with common neurological and nonneurological diseases. Despite entering the differential diagnosis of the most common neurological diseases, mitochondrial disorders themselves are rare, and the diagnostic approach is complex, time consuming, and expensive. Following a detailed history, examination, and clinical investigations, many patients require an invasive biopsy of clinically affected tissue before samples are dispatched on ice to a limited number of laboratories worldwide. Although a positive biochemical result can substantiate a clinical diagnosis (muscle histochemistry or respiratory chain complex analysis), the results are often inconclusive. Subtle histochemical defects can occur as part of healthy aging, and individuals deconditioned from any cause can have low respiratory chain enzyme activities in skeletal muscle. However, pursuing a genetic diagnosis is important because similar clinical and biochemical phenotypes can be sporadic, maternally inherited (through mitochondrial DNA [mtDNA]), autosomal dominant, autosomal recessive, and occasionally X-linked. Thus, defining the underlying gene defect can sway the recurrence risks from zero to very high and everything in between. Targeted genetic analysis typically proceeds on a stepby-step basis, guided by the clinical picture and the biochemical profile. A thorough laboratory workup takes months or years and is still inconclusive in approximately one-third of cases. If ever there was a need for a genetic revolution, mitochondrial disorders have a strong case.

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Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

Cited by 326 publications

References 38 publications

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy

The Effect of Neurological Genomics and Personalized Mitochondrial Medicine

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