2023
P154 The generation of a GNE myopathy patient-derived biobank enables the study of disease-relevant cellular phenotypes across multiple pathogenic variants
Koczwara K, Lake N, Huang S, DeSimone A, Pajusalu S, Branford K, Hallak D, Woodman K, Xu J, Lek A, Best H, Habib A, Avelar J, Martin V, Mozaffar T, Shieh P, Weisleder N, Lek M. P154 The generation of a GNE myopathy patient-derived biobank enables the study of disease-relevant cellular phenotypes across multiple pathogenic variants. Neuromuscular Disorders 2023, 33: s138. DOI: 10.1016/j.nmd.2023.07.286.Peer-Reviewed Original ResearchPathogenic mutationsCRISPR/Cas9 knockoutDisease-relevant cell typesSialic acid biosynthesis pathwayCellular disease modelsMyogenic cell lineCell linesGNE myopathy patientsPatient-derived cell linesGNE activityWhole-genome sequencingGNE proteinPathogenic variantsBiosynthesis pathwayDisease-relevant cellular phenotypesCellular functionsMyogenic lineageCellular phenotypesRNA sequencingBifunctional enzymeGenome sequencingMultiple pathogenic variantsReduced enzymatic activitySkeletal muscle atrophyMyopathy patients
2022
Neuromuscular disorders: finding the missing genetic diagnoses
Koczwara KE, Lake NJ, DeSimone AM, Lek M. Neuromuscular disorders: finding the missing genetic diagnoses. Trends In Genetics 2022, 38: 956-971. PMID: 35908999, DOI: 10.1016/j.tig.2022.07.001.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHigh-throughput functional screeningDiscovery of hundredsGenetic diagnosisNMD genesNext-generation sequencingFunctional screeningSequencing technologiesPathogenic variantsNeuromuscular disordersGroup of diseasesGenesSequencingFuture approachesLarge numberRecent advancementsDiscoveryVariantsYield
2019
A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant
Lake N, Formosa L, Stroud D, Ryan M, Calvo S, Mootha V, Morar B, Procopis P, Christodoulou J, Compton A, Thorburn D. A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant. Human Mutation 2019, 40: 893-898. PMID: 30981218, PMCID: PMC6661004, DOI: 10.1002/humu.23753.Peer-Reviewed Original ResearchConceptsProtein-truncating variantsCI assemblyC-terminusLeigh syndromeMutant proteinsKnockout cellsDisease genesUncharacterized variantsHypomorphic effectPathogenic variantsLeigh-like syndromeMitochondrial diseaseWhole-exome sequencingGenomic criteriaFunctional studiesAmino acidsGenesTIMMDC1Homozygous nonsense variantPatient's clinical phenotypeClinical phenotypeExome sequencingNonsense variantMedical GeneticsDual diagnosisLeigh syndrome caused by mutations in MTFMT is associated with a better prognosis
Hayhurst H, de Coo I, Piekutowska‐Abramczuk D, Alston C, Sharma S, Thompson K, Rius R, He L, Hopton S, Ploski R, Ciara E, Lake N, Compton A, Delatycki M, Verrips A, Bonnen P, Jones S, Morris A, Shakespeare D, Christodoulou J, Wesol‐Kucharska D, Rokicki D, Smeets H, Pronicka E, Thorburn D, Gorman G, McFarland R, Taylor R, Ng Y. Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis. Annals Of Clinical And Translational Neurology 2019, 6: 515-524. PMID: 30911575, PMCID: PMC6414492, DOI: 10.1002/acn3.725.Peer-Reviewed Original ResearchConceptsPathogenic variantsLeigh syndromeSubcortical white matter abnormalitiesNew casesFrequent initial manifestationLast clinical reviewRetrospective cohort studyBasal ganglia changesWhite matter abnormalitiesRespiratory chain deficiencyBi-allelic pathogenic variantsMitochondrial methionyl-tRNA formyltransferaseMolecular genetic findingsMilder clinical phenotypeInitial manifestationBrainstem lesionsCohort studyMedian ageBetter prognosisChain deficiencyMotor symptomsClinical reviewDisease progressionMultiple respiratory chain deficiencyMuscle biopsy