Proactive Variant Effect Mapping Aids Diagnosis in Pediatric Cardiac Arrest

Floyd, Brendan J.; Kannankeril, Prince J.; Glazer, Andrew M.; Reuter, Chloe; MacRae, Calum A.; Ashley, Euan A.; Roden, Dan M.; Roth, Frederick P.; Parikh, Victoria N.

doi:10.1161/circgen.122.003792

Cited by 4 publications

(6 citation statements)

References 5 publications

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“…Despite all of these caveats, assays based on the expression of human cDNA in yeast can provide excellent empirical performance in identifying pathogenic variation [22] [19] [32] [65]. Here, we showed that approximately half of CHK2’s known pathogenic missense variants could be identified at a stringency achieving 90% balanced precision, i.e., if a balanced training set is applied, we would expect that 90% of the map’s inferred-pathogenic variants would in fact be pathogenic.…”

Section: Discussionmentioning

confidence: 99%

A missense variant effect map for the human tumour suppressor protein CHK2

Gebbia,

Zimmerman,

Jiang

et al. 2024

Preprint

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The tumour suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair and inducing apoptosis. CHK2 phosphorylation of the tumour suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and multiple other cancer types. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of a S. cerevisiae lacking its ortholog RAD53, we generated a systematic missense variant effect map for CHEK2 missense variation. Map scores reflect known biochemical features of CHK2 and exhibit good performance in separating pathogenic from benign clinical missense variants. Thus, the missense variant effect map for CHK2 offers value in understanding both known and yet-to-be-observed CHK2 variants.

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Section: Discussionmentioning

confidence: 99%

A missense variant effect map for the human tumour suppressor protein CHK2

Gebbia,

Zimmerman,

Jiang

et al. 2024

Preprint

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“…Additionally, functional genomics methods are increasingly used to uncover patterns that aid in variant calling. 55,56 Combining functional imaging with artificial intelligencebased methods of variant assessment has the potential to reduce the VUS burden. Patient-specific induced pluripotent stem cell models can be utilized to investigate the pathogenesis of LQTS in vitro, and test drug efficacy and toxicity in a diseasespecific context.…”

Section: Unfilled Gaps In Clinical Practicementioning

confidence: 99%

Section: Challenges In Genetic Testingmentioning

confidence: 99%

Unraveling Complexities in Genetically Elusive Long QT Syndrome

Asatryan,

Murray,

Gasperetti

et al. 2024

Circ: Arrhythmia and Electrophysiology

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Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.

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“…Here, we implemented two high-throughput functional assays to study the KCNH2 -LQT2 relationship: 1) Multiplexed Assays of Variant Effect (MAVE) 5,6 , and 2) Automated Patch Clamping (APC) 7 . The MAVE probed the effect on protein trafficking of nearly all possible KCNH2 missense variants, providing prospective evidence for unascertained variant future classification 8 . APC recorded detailed effects on variant protein electrophysiological function after clinical ascertainment.…”

Section: Main Textmentioning

confidence: 99%

Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping forKCNH2-LQTS Risk Stratification

O’Neill,

Ng,

Aizawa

et al. 2024

Preprint

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Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data. Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,796 missense variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort. Results: Traditional risk factors of QT interval adjusted for heart rate (Hazard Ratio 1.09 [1.07-1.12]) and sex (HR 0.60 [0.47-0.76]) were most significant for predicting events; however, variant-specific current density (HR 0.44 [0.26-0.70]) and estimates of LQTS penetrance (HR 1.93; [1.13-3.39]) were independently predictive of severe cardiac events when controlling for patient-specific features. Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease.

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Proactive Variant Effect Mapping Aids Diagnosis in Pediatric Cardiac Arrest

Cited by 4 publications

References 5 publications

A missense variant effect map for the human tumour suppressor protein CHK2

A missense variant effect map for the human tumour suppressor protein CHK2

Unraveling Complexities in Genetically Elusive Long QT Syndrome

Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping forKCNH2-LQTS Risk Stratification

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