2024
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
Lee A, Ayers L, Kosicki M, Chan W, Fozo L, Pratt B, Collins T, Zhao B, Rose M, Sanchis-Juan A, Fu J, Wong I, Zhao X, Tenney A, Lee C, Laricchia K, Barry B, Bradford V, Jurgens J, England E, Lek M, MacArthur D, Lee E, Talkowski M, Brand H, Pennacchio L, Engle E. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders. Nature Communications 2024, 15: 8268. PMID: 39333082, PMCID: PMC11436875, DOI: 10.1038/s41467-024-52463-7.Peer-Reviewed Original ResearchConceptsNon-coding variantsCranial motor neuronsMendelian disordersIn vivo transgenic assayPredictor of enhancer activityCis-regulatory elementsMulti-omic frameworkWhole-genome sequencingEnhanced activityVariant discoveryGenome sequenceChromatin accessibilityPutative enhancersHistone modificationsRegulatory elementsGene expression assaysGene predictionTransgenic assaysEpigenomic profilingMendelian casesExpression assaysMutational enhancementCongenital cranial dysinnervation disordersCell typesFunctional impact
2017
Improving genetic diagnosis in Mendelian disease with transcriptome sequencing
Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, Bolduc V, Waddell LB, Sandaradura SA, O’Grady G, Estrella E, Reddy HM, Zhao F, Weisburd B, Karczewski KJ, O’Donnell-Luria A, Birnbaum D, Sarkozy A, Hu Y, Gonorazky H, Claeys K, Joshi H, Bournazos A, Oates EC, Ghaoui R, Davis MR, Laing NG, Topf A, Consortium G, Kang PB, Beggs AH, North KN, Straub V, Dowling JJ, Muntoni F, Clarke NF, Cooper ST, Bönnemann CG, MacArthur DG. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Science Translational Medicine 2017, 9 PMID: 28424332, PMCID: PMC5548421, DOI: 10.1126/scitranslmed.aal5209.Peer-Reviewed Original ResearchConceptsTranscriptome sequencingRNA-seqCurrent diagnostic ratePrior genetic analysisTranscript level changesTriple-helical domainDeep intronic regionsWhole-genome sequencingSplice-altering variantsInterpretation of variantsRepeat motifsGenomic analysisHelical domainMendelian disease diagnosisGenetic analysisMendelian diseasesIntronic regionsSkeletal muscle samplesSequencingRare disease diagnosisIntronic mutationOverall diagnosis rateStandard diagnostic approachRare muscle disorderComplementary diagnostic tool
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