scholarly journals Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 855 ◽  
Author(s):  
Adrián González-Quintana ◽  
Inés García-Consuegra ◽  
Amaya Belanger-Quintana ◽  
Pablo Serrano-Lorenzo ◽  
Alejandro Lucia ◽  
...  
Keyword(s):  
Maximal Oxygen Consumption ◽  
Brain Magnetic Resonance Imaging ◽  
Leigh Syndrome ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Resonance Imaging ◽  
Atp Production ◽  
Novel Variants ◽  
Next Generation Sequencing Ngs ◽  
Spastic Tetraparesis ◽  
Generation Sequencing

Leigh syndrome (LS) usually presents as an early onset mitochondrial encephalopathy characterized by bilateral symmetric lesions in the basal ganglia and cerebral stem. More than 75 genes have been associated with this condition, including genes involved in the biogenesis of mitochondrial complex I (CI). In this study, we used a next-generation sequencing (NGS) panel to identify two novel biallelic variants in the NADH:ubiquinone oxidoreductase subunit A13 (NDUFA13) gene in a patient with isolated CI deficiency in skeletal muscle. Our patient, who represents the second family report with mutations in the CI NDUFA13 subunit, presented with LS lesions in brain magnetic resonance imaging, mild hypertrophic cardiomyopathy, and progressive spastic tetraparesis. This phenotype manifestation is different from that previously described in the first NDUFA13 family, which was predominantly characterized by neurosensorial symptoms. Both in silico pathogenicity predictions and oxidative phosphorylation (OXPHOS) functional findings in patient’s skin fibroblasts (delayed cell growth, isolated CI enzyme defect, decreased basal and maximal oxygen consumption and as well as ATP production, together with markedly diminished levels of the NDUFA13 protein, CI, and respirasomes) suggest that these novel variants in the NDUFA13 gene are the underlying cause of the CI defect, expanding the genetic heterogeneity of LS.

A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome

2020 ◽  
Vol 58 (11) ◽  
pp. 1809-1817
Author(s):  
Miaomiao Du ◽  
Xiujuan Wei ◽  
Pu Xu ◽  
Anran Xie ◽  
Xiyue Zhou ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Clinical Symptoms ◽  
Lactate Production ◽  
Mitochondrial Diseases ◽  
Leigh Syndrome ◽  
Extracellular Lactate ◽  
Next Generation Sequencing Ngs ◽  
Mutant Cells ◽  
Generation Sequencing

AbstractObjectivesLeigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete.MethodsNext-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant.ResultsA novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells.ConclusionsA novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.

scholarly journals Methylmalonic Acidemia with Novel MUT Gene Mutations

2017 ◽  
Vol 2017 ◽  
pp. 1-2
Author(s):  
Inusha Panigrahi ◽  
Savita Bhunwal ◽  
Harish Varma ◽  
Simranjeet Singh
Keyword(s):  
Sanger Sequencing ◽  
Gene Mutations ◽  
Methylmalonic Acidemia ◽  
Feeding Problems ◽  
Novel Variants ◽  
Mut Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Poor Weight Gain

A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations.

scholarly journals Prenatal Diagnosis and Genetic Analysis of a Fetus with Joubert Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Jingjing Xiang ◽  
Lili Zhang ◽  
Wei Jiang ◽  
Qin Zhang ◽  
Ting Wang ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Sanger Sequencing ◽  
Missense Variant ◽  
Joubert Syndrome ◽  
Prenatal Ultrasound ◽  
Resonance Imaging ◽  
Targeted Next Generation Sequencing ◽  
Magnetic Resonance Imaging Mri ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Objective. To diagnose and explore the genetic cause of Joubert syndrome (JS) in a fetus. Methods. Prenatal ultrasound and magnetic resonance imaging (MRI) examinations were performed, and genetic analysis was conducted using targeted next-generation sequencing (NGS) and Sanger sequencing. Results. Prenatal ultrasound and MRI examinations showed cerebellar vermis hypoplasia and molar tooth sign (MTS); hence the fetus was diagnosed with JS. Further genetic analysis revealed a known missense variant (c.3599C>T, p.A1200V) and a novel missense variant (c.3857G>A, p.R1286H) in the C5orf42 gene of the fetus. Conclusion. Our study provides insights into prenatal and early diagnosis of JS and expands the variation spectrum of C5orf42 gene.

scholarly journals Identification of Gene Variants Related to Malignant Hyperthermia in Han Chinese People by Next-Generation Sequencing.

2020 ◽  
Author(s):  
Jianxiong Zhang ◽  
Lina Fu ◽  
Dandan Li ◽  
Xuewei Cheng ◽  
Mengmeng Hu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Malignant Hyperthermia ◽  
Protein Function ◽  
Targeted Sequencing ◽  
Next Generation ◽  
Novel Variants ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background: Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by anesthesia. In recent years, next generation sequencing(NGS) technology, targeted sequencing approaches have been used to identify regions related to MH and can not only detect known MH variant sites but also allow the exploration of novel MH-related variants.Methods: Twenty-four volunteer’s blood samples were collected, genomic DNA was then extracted, target regions were amplified, and through targeted sequencing of these target regions, both known and novel variants were identified, and analysis of these variants identified some that may damage protein function. Online prediction tools were also used to determine the possibility of variants that may cause MH.Results: We performed next-generation sequencing of 53 positions on 4 genes, in which 36 variants of the RYR1 gene were found. Three of these caused a change in the amino acid sequence. Additionally, 11 variants of the CACNA1S gene were found, of which 3 led to amino acid sequence changes. Five variants of the JSRP1 gene were found, and four variants caused the amino acid sequence to change.Conclusions: In healthy volunteers, variants in RYR1 and CACNA1S were more common, and variants in JSRP1 more commonly had amino acid sequence changes. Whether a variant is pathogenic can be predicted using a prediction website, but the sensitivity and specificity still need to be improved.

Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients

2021 ◽  
Vol 21 ◽  
Author(s):  
Sara Momtazmanesh ◽  
Elham Rayzan ◽  
Samaneh Zoghi ◽  
Sepideh Shahkarami ◽  
Rasol Molatefi ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Case Series ◽  
Skin Lesions ◽  
Hematopoietic Stem ◽  
Whole Exome ◽  
Novel Variants ◽  
Dock8 Deficiency ◽  
Polymerase Chain ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. Objective: In this study, we report seven patients with consanguineous parents with five novel variants within the DOCK8 gene. Methods: For genetic analysis, we performed Whole Exome Sequencing (WES), or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) was used. Results: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA , reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells, and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. Conclusion: We reported novel variants within the DOCK8 gene and highlighted risk of aneurysms in these patients, which have been rarely reported in these patients.

scholarly journals Orthogonal Comparison of Four Plasma NGS Tests With Tumor Suggests Technical Factors are a Major Source of Assay Discordance

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Daniel Stetson ◽  
Ambar Ahmed ◽  
Xing Xu ◽  
Barrett R.B. Nuttall ◽  
Tristan J. Lubinski ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
False Negative ◽  
Variant Calling ◽  
Circulating Tumor Dna ◽  
Orthogonal Comparison ◽  
Novel Variants ◽  
Technical Factors ◽  
Next Generation Sequencing Ngs ◽  
Biologic Factors ◽  
Generation Sequencing

PURPOSE Discordance between plasma and tumor variant calling has been attributed primarily to tumor heterogeneity, whereas technical variables remain largely unexplored. MATERIALS AND METHODS To measure these variables, we tested four next-generation sequencing (NGS) gene panel assays for mutations in circulating tumor DNA (ctDNA) using replicate sets of 24 plasma samples and compared the results with matched tumor-normal tissue pairs. RESULTS Our orthogonal approach identified false-negative (FN) and false-positive (FP) variants with high confidence and revealed substantial variability among the ctDNA assays, with a range of sensitivity (38% to 89%) and positive predictive value (36% to 80%). Most discordance in our cross-vendor study was observed below 1% variant allele frequency. FP variants displayed mutational biases and tended to be novel variants not found in somatic databases. Of the 56 unique variants called by all four ctDNA assays, 41 (68%) resulted from technical discordance. CONCLUSION These findings suggest that most NGS assay discordance is a result of technical variations and, to a lesser extent, biologic factors such as clonal hematopoiesis of indeterminate potential and tumor heterogeneity.

scholarly journals Yield of Rare Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1061
Author(s):  
Miruna Mihaela Micheu ◽  
Nicoleta-Monica Popa-Fotea ◽  
Nicoleta Oprescu ◽  
Stefan Bogdan ◽  
Monica Dan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hypertrophic Cardiomyopathy ◽  
Rare Variants ◽  
Causal Variant ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Novel Variants ◽  
Next Generation Sequencing Ngs ◽  
First Time ◽  
Generation Sequencing

Background: The aim of this study was to explore the rare variants in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM). Methods: Forty-five unrelated probands with HCM were screened by targeted next generation sequencing (NGS) of 47 core and emerging genes connected with HCM. Results: We identified 95 variants with allele frequency < 0.1% in population databases. MYBPC3 and TTN had the largest number of rare variants (17 variants each). A definite genetic etiology was found in 6 probands (13.3%), while inconclusive results due to either known or novel variants were established in 31 cases (68.9%). All disease-causing variants were detected in sarcomeric genes (MYBPC3 and MYH7 with two cases each, and one case in TNNI3 and TPM1 respectively). Multiple variants were detected in 27 subjects (60%), but no proband carried more than one causal variant. Of note, almost half of the rare variants were novel. Conclusions: Herein we reported for the first time the rare variants identified in core and putative genes associated with HCM in a cohort of Romanian unrelated adult patients. The clinical significance of most detected variants is yet to be established, additional studies based on segregation analysis being required for definite classification.

Nonketotic Hyperglycemic Chorea in a 10-Year-Old Asian Boy with Diabetes Mellitus

2020 ◽  
Author(s):  
Julia Marian ◽  
Firdous Rizvi ◽  
Lily Q. Lew
Keyword(s):  
Diabetes Mellitus ◽  
Parietal Lobe ◽  
Rare Complication ◽  
Brain Magnetic Resonance Imaging ◽  
Food Allergies ◽  
Developmental Venous Anomaly ◽  
Venous Anomaly ◽  
Resonance Imaging ◽  
Focal Lesions

AbstractNonketotic hyperglycemic chorea-ballism (NKHCB), also known as diabetic striato-pathy (DS) by some, is a rare complication of diabetes mellitus and uncommon in children. We report a case of a 10 11/12-year-old boy of Asian descent with uncontrolled type 1 diabetes mellitus (T1DM), Hashimoto's thyroiditis, and multiple food allergies presenting with bilateral chorea-ballism. His brain magnetic resonance imaging revealed developmental venous anomaly in right parietal lobe and right cerebellum, no focal lesions or abnormal enhancements. Choreiform movements resolved with correction of hyperglycemia. Children and adolescents with a movement disorder should be evaluated for diabetes mellitus, especially with increasing prevalence and insidious nature of T2DM associated with obesity.

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