2021
DOI: 10.1101/2021.01.14.21249850
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Combinatorial clinically driven blood biomarker functional genomics significantly enhances genotype-phenotype resolution and diagnostics in neuromuscular disease

Abstract: Purpose50-60% of neuromuscular-disease patients remain undiagnosed even after extensive genetic testing that hinders precision-medicine/clinical-trial-enrollment. Importantly, those with DNA-based molecular diagnosis often remain without known molecular mechanism driving different degrees of disease severity that hinders patient stratification and trial-readiness. These are due to: a) clinical-genetic-heterogeneity (eg: limb-girdle-muscular-dystrophies(LGMDs)>30-subtypes); b) high-prevalence of variants-of-… Show more

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“…In large cohorts, transcript abundance can also be used to analyze downstream effects of some pathogenic variants and characterize pathways involved in disease [ 48 , 49 ]. Even where a likely pathogenic variant is identified by DNA analysis, RNAseq can provide supporting evidence that the transcript is affected, and may be used to establish that both alleles are affected in trans by different mutations [ 50 , 51 ]. Although peripheral blood is a mixture of dozens of cell types, so long as the defect is observed in one or more of the major leukocyte or monocyte populations, bulk RNAseq should be a useful source of clinically actionable information.…”
Section: Introductionmentioning
confidence: 99%
“…In large cohorts, transcript abundance can also be used to analyze downstream effects of some pathogenic variants and characterize pathways involved in disease [ 48 , 49 ]. Even where a likely pathogenic variant is identified by DNA analysis, RNAseq can provide supporting evidence that the transcript is affected, and may be used to establish that both alleles are affected in trans by different mutations [ 50 , 51 ]. Although peripheral blood is a mixture of dozens of cell types, so long as the defect is observed in one or more of the major leukocyte or monocyte populations, bulk RNAseq should be a useful source of clinically actionable information.…”
Section: Introductionmentioning
confidence: 99%