A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

Sun, Song; Verby, Marta; Wu, Yingzhou; Wang, Yang; Coté, Atina G.; Fotiadou, Iosifina; Kitaygorodsky, Julia; Vidal, Marc; Rine, Jasper; Ješina, Pavel; Kožich, Viktor; Roth, Frederick P.

doi:10.1186/s13073-020-0711-1

Cited by 50 publications

(61 citation statements)

References 71 publications

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“… 78 Most other human genes subjected to full-length mutational scans thus far have shown substantially higher overall constraint: for instance, 40.5% of missense variants in the pharmacogene NUDT15 scored as damaging, 62 as were 39% of variants in the homocysteine metabolic factor CBS . 79 A recent activity-agnostic protein stability screen showed the fraction of missense variants with substantially destabilizing effects to range from 25.1% to 43.1% across three different genes; 62 , 80 these could be taken as a lower bound given that an unknown fraction of true LoF variants may remain stable.…”

Section: Discussionmentioning

confidence: 99%

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk

Jia

Burugula

Chen

et al. 2021

The American Journal of Human Genetics

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The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed ''variants of uncertain significance'' (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians' interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the $1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.

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Section: Discussionmentioning

confidence: 99%

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk

Jia

Burugula

Chen

et al. 2021

The American Journal of Human Genetics

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“…Recent deployments of functional assays to study protein variants have proven to be highly accurate at predicting pathogenicity when results are benchmarked to clinically established annotations. A yeast complementation assay was used to create a variant-effect map for CBS , the gene underlying classical homocystinuria ( 67 ). In addition to predicting pathogenic variants more accurately than computational models, the authors show that the degree of assay impairment correlates with the age of disease onset and severity in patients.…”

Section: Developing Multiplex Assays With High Clinical Relevancementioning

confidence: 99%

Linking genome variants to disease: scalable approaches to test the functional impact of human mutations

Findlay

2021

Human Molecular Genetics

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The application of genomics to medicine has accelerated the discovery of mutations underlying disease and enhanced our knowledge of the molecular underpinnings of diverse pathologies. As the amount of human genetic material queried via sequencing has grown exponentially in recent years, so too has the number of rare variants observed. Despite progress, our ability to distinguish which rare variants have clinical significance remains limited. Over the last decade, however, powerful experimental approaches have emerged to characterise variant effects orders of magnitude faster than before. Fuelled by improved DNA synthesis and sequencing, and more recently by CRISPR/Cas9 genome editing, multiplex functional assays provide a means of generating variant effect data in wide-ranging experimental systems. Here, I review recent applications of multiplex assays that link human variants to disease phenotypes and describe emerging strategies that will enhance their clinical utility in coming years.

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“…Most of the currently available tools, v.g. SIFT (Vaser, Adusumalli, Leng, Sikic, & Ng, 2016), PolyPhen (Adzhuvei, et al, 2010, and Revel (Ioannidis, et al, 2016) are designed to yield scores for missense type variants exclusively, resulting in a lower performance in the dataset as it includes diverse variant consequence types. Only a third of the variants of this dataset are missense type, and there are significant numbers of synonymous, non coding transcript exon, intron, and splice variants.…”

Section: High Performance Among Different Variant Consequence Typesmentioning

confidence: 99%

Machine Learning Models for Accurate Prioritization of Variants of Uncertain Significance

Mahecha¹,

Núñez²,

Lattig³

et al. 2020

Preprint

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The growing use of new generation sequencing technologies on genetic diagnosis has produced an exponential increase in the number of Variants of Uncertain Significance (VUS). In this manuscript we compare three machine learning methods to classify VUS as Pathogenic or No pathogenic, implementing a Random Forest (RF), a Support Vector Machine (SVM), and a Multilayer Perceptron (MLP). To train the models, we extracted 82,463 high quality variants from ClinVar, using 9 conservation scores, the loss of function tool and allele frequencies. For the RF and SVM models, hyperparameters were tuned using cross validation with a grid search. The three models were tested on a set of 5,537 variants that had been classified as VUS any time along the last three years but had been reclassified in august 2020. The three models yielded superior accuracy on this set compared to the benchmarked tools. The RF based model yielded the best performance across different variant types and was used to create VusPrize, an open source software tool for prioritization of variants of uncertain significance. We believe that our model can improve the process of genetic diagnosis on research and clinical settings.

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A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

Cited by 50 publications

References 71 publications

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk

Linking genome variants to disease: scalable approaches to test the functional impact of human mutations

Machine Learning Models for Accurate Prioritization of Variants of Uncertain Significance

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