An integrated, scaled approach to resolve TSC2 variants of uncertain significance
Biar, C. G.; Wang, Z. R.; Camp, N. D.; Holmes, D. L.; Wheelock, M. K.; Pendyala, S.; McGee, A. V.; Gupta, P.; McEwen, A. E.; Tejura, M.; Richardson, M. E.; Weyandt, J. D.; Coleman, T.; Stewart, R.; Zeiberg, D.; Vandi, A. J.; Dawson, S.; Radivojac, P.; Starita, L. M.; Carvill, G. L.; James, R. G.; Fowler, D. M.; Calhoun, J. D.
Show abstract
Obtaining a precise genetic tuberous sclerosis diagnosis is a challenge as many missense TSC2 variants are variants of uncertain significance (VUS). VUS in TSC2 have been resolved by one-at-a-time functional assays, but these assays cannot scale to the 3,634 TSC2 missense VUS observed so far. To address this challenge, we used massively parallel sequencing to measure the steady-state abundance of almost 9,000 TSC2 missense variants and developed an mTOR pathway activity assay using genome editing and cell sorting to generate activity scores for 391 missense variants. 1,288 of 8,891 (14.49%) missense variants assayed had altered TSC2 abundance, and 69 of 391 (17.65%) missense variants assayed had altered mTOR pathway activity. Calibration and integration of these data into classification of variants identified in a clinical cohort putatively reclassified 212 of 276 (76.8%) TSC2 missense VUS. These datasets will lead to improved genetic diagnosis of tuberous sclerosis with potential positive impacts on the clinical management of patients and their families.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency 95%
- Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin 95%
- Transcriptome-wide outlier approach identifies individuals with minor spliceopathies 94%
Similar papers in this journal
- Long-read genome sequencing for the diagnosis of neurodevelopmental disorders 95%
- Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity 93%
- Identification and validation of novel candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas 93%
Similar papers in this journal
Similar papers in this journal
- ParSE-seq: A Calibrated Multiplexed Assay to Facilitate the Clinical Classification of Putative Splice-altering Variants 95%
- Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature 94%
- Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction 94%
Similar papers in this journal
- A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project. 94%
- Systematic analysis of genetic and phenotypic characteristics reveals antisense oligonucleotide therapy potential for one-third of neurodevelopmental disorders 94%
- Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of diverse feature set 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.