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1.
Hum Mutat ; 40(7): 893-898, 2019 07.
Article in English | MEDLINE | ID: mdl-30981218

ABSTRACT

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C-terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein-truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C-terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.


Subject(s)
Leigh Disease/genetics , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Sequence Deletion , Early Diagnosis , Gene Knockout Techniques , HEK293 Cells , Homozygote , Humans , Mitochondrial Precursor Protein Import Complex Proteins , Pyruvate Dehydrogenase Complex/genetics , Exome Sequencing
2.
Seizure ; 59: 132-140, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29852413

ABSTRACT

PURPOSE: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants. RESULTS: The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants. CONCLUSION: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.


Subject(s)
Epilepsy/diagnosis , Epilepsy/genetics , Genetic Testing , High-Throughput Nucleotide Sequencing , Adolescent , Child , Child, Preschool , Cost-Benefit Analysis , Epilepsy/economics , Female , Genetic Predisposition to Disease , Genetic Testing/economics , Genetic Testing/methods , Genetic Variation , High-Throughput Nucleotide Sequencing/economics , Humans , Infant , Male , Phenotype , Retrospective Studies
3.
Am J Hum Genet ; 94(2): 209-22, 2014 Feb 06.
Article in English | MEDLINE | ID: mdl-24462369

ABSTRACT

Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin. They differed from individuals with SURF1 mutations in having seizures as a prominent feature. Complementation analysis suggested they had mutation(s) in the same gene but targeted massively parallel sequencing (MPS) of 1,034 genes encoding known mitochondrial proteins failed to identify a likely candidate. Linkage and haplotype analyses mapped the location of the gene to chromosome 19 and targeted MPS of the linkage region identified a homozygous c.3G>C (p.Met1?) mutation in C19orf79. Abolishing the initiation codon could potentially still allow initiation at a downstream methionine residue but we showed that this would not result in a functional protein. We confirmed that mutation of this gene was causative by lentiviral-mediated phenotypic correction. C19orf79 was recently renamed PET100 and predicted to encode a complex IV biogenesis factor. We showed that it is located in the mitochondrial inner membrane and forms a ∼300 kDa subcomplex with complex IV subunits. Previous proteomic analyses of mitochondria had overlooked PET100 because its small size was below the cutoff for annotating bona fide proteins. The mutation was estimated to have arisen at least 520 years ago, explaining how the families could have different religions and different geographic origins within Lebanon.


Subject(s)
Cytochrome-c Oxidase Deficiency/ethnology , Cytochrome-c Oxidase Deficiency/genetics , Founder Effect , Leigh Disease/ethnology , Leigh Disease/genetics , Mitochondrial Proteins/genetics , Chromosomes, Human, Pair 19/genetics , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Cytochrome-c Oxidase Deficiency/complications , DNA, Mitochondrial/genetics , DNA, Mitochondrial/isolation & purification , Female , Genetic Complementation Test , Genetic Linkage , Genome-Wide Association Study , Haplotypes , Homozygote , Humans , Infant , Lebanon , Leigh Disease/complications , Male , Mitochondria/genetics , Mitochondria/metabolism , Mutation , Pedigree , Polymorphism, Single Nucleotide , Proteomics , Sequence Analysis, DNA
4.
Mitochondrion ; 11(1): 104-7, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20708716

ABSTRACT

Mutations in the polymerase γ (POLG) gene are among the most common causes of mitochondrial disease and more than 160 POLG mutations have been reported. However, a large proportion of patients suspected of having POLG mutations only have one (heterozygous) definitive pathogenic mutation identified. Using oligonucleotide array CGH, we identified a compound heterozygous large intragenic deletion encompassing exons 15-21 of this gene in a child with Alpers syndrome due to mtDNA depletion. This is the first large POLG deletion reported and the findings show the clinical utility of using array CGH in cases where a single heterozygous mutation has been identified in POLG.


Subject(s)
Comparative Genomic Hybridization/methods , DNA-Directed DNA Polymerase/genetics , Diffuse Cerebral Sclerosis of Schilder/genetics , Mutation , Oligonucleotide Array Sequence Analysis/methods , Child, Preschool , DNA Polymerase gamma , DNA, Mitochondrial/genetics , Exons/genetics , Fatal Outcome , Female , Heterozygote , Humans
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