Author Correction: Transcript expression-aware annotation improves rare variant interpretation

Cummings, Beryl B.; Team, Genome Aggregation Database Production; Karczewski, Konrad J.; Kosmicki, Jack A.; Seaby, Eleanor G.; Watts, Nicholas A.; Singer-Berk, Moriel; Mudge, Jonathan M.; Karjalainen, Juha; Satterstrom, F. Kyle; O’Donnell-Luria, Anne H.; Poterba, Timothy; Seed, Cotton; Solomonson, Matthew; Alföldi, Jessica; Daly, Mark J.; MacArthur, Daniel G.

doi:10.1038/s41586-020-03175-7

Cited by 23 publications

(47 citation statements)

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“…This suggests that the signal is not solely driven by the most pathogenic variants nor direct rare variant effects on splicing. These results extend the previous work, comparing different exons and showing accumulation of stop-gained variants on those with lower inclusion (Cummings et al 2020). Here, observe a similar pattern when comparing different individuals within a given exon, consistent with the hypothesis that the penetrance of coding alleles is reduced when they fall on more lowly included exons.…”

Section: Resultssupporting

confidence: 91%

“…Alternative splicing is responsible for the great diversity of isoform structures observed across human tissues and cell types (Keren et al 2010). With regard to coding variant interpretation, exons with lower expression have been shown to be less likely to harbor pathogenic variants, while ubiquitously included exons can be prioritized for gene disrupting rare variants (Cummings et al 2020). Autistic individuals with variants on the same exons have been shown to have remarkably similar disease phenotypes, putatively due to the variants having similar effects on gene dosage or function, a notable finding given the extreme heterogeneity of the condition (Chiang et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Einson

Glinos

Boerwinkle

et al. 2023

Preprint

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Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Einson

Glinos

Boerwinkle

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…7,[13][14][15] This enrichment is particularly striking in genes where true LoF variants are well-established to cause genetic disease that is not compatible with participation in common disease studies, thus not expected in population databases like gnomAD. [16][17][18] Such high error rates complicate studies leveraging pLoF variants seen in large cohorts to explore human gene function, an approach that has proven extremely valuable for the identification and validation of potential therapeutic targets. 19 While automated approaches to pLoF variant filtering remove a substantial fraction of errors, 7,18 multiple studies have demonstrated the value of deep manual curation of pLoF variants to identify evasion modes and sequencing artifacts missed by these automated tools.…”

Section: Introductionmentioning

confidence: 99%

Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data

Singer-Berk

Gudmundsson

Baxter

et al. 2023

Preprint

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Predicted loss of function (pLoF) variants are highly deleterious and play an important role in disease biology, but many of these variants may not actually result in loss-of-function. Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines's PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 autosomal recessive disease-genes from the Genome Aggregation Database (gnomAD, v2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in low per-base expression (pext) score regions, or the presence of cryptic splice rescues. Variants predicted to be potential artifacts or to evade LoF were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of LoF evading variants assessed, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines, and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.

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“…UTMOST 18 modestly improves average imputation r 2 across tissues over PrediXcan by 36.8% 18 . Moreover, genes associated with Mendelian diseases are likely depleted for common cis-eQTLs 40,[51][52][53][54][55] . Future studies could potentially incorporate methods that use rare eQTLs 53 , trans-eQTLs, and epigenetic information 56 to predict gene expression.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

Wigdor

Samocha

Eberhardt

et al. 2023

Preprint

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Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene,RAB2A, that passed multiple testing correction (p = 6.7×10-7). We then investigated whethercis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7×10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that commoncis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

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Author Correction: Transcript expression-aware annotation improves rare variant interpretation

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03175-7

Cited by 23 publications

References 0 publications

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data

Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

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