Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

Sahajpal, Nikhil; Lai, Chi-Yu; Hastie, Alex; Mondal, Ashis; Dehkordi, Siavash R.; Made, Caspar I. van der; Fédrigo, Olivier; Al-Ajli, Farooq Omar Maan; Jalnapurkar, Sawan; Byrska-Bishop, Marta; Kanagal‐Shamanna, Rashmi; Levy, Brynn; Schieck, Maximilian; Illig, Thomas; Bacanu, Silviu‐Alin; Chou, Janet; Randolph, Adrienne G.; Rojiani, Amyn M.; Zody, Michael C.; Brownstein, Catherine A.; Beggs, Alan H.; Bafna, Vineet; Jarvis, Erich D.; Hoischen, Alexander; Chaubey, Alka; Kolhe, Ravindra

doi:10.1016/j.isci.2022.103760

Cited by 17 publications

(9 citation statements)

References 81 publications

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“…Further improvements include time dependent predictions allowing for an online monitoring of patients, taking the patient history into account. We will also check whether the incorporation of genetic risk factors associated with a severe Covid-19 progression [ 41 ] can improve the predictions even further.…”

Section: Discussionmentioning

confidence: 99%

Machine learning models for predicting severe COVID-19 outcomes in hospitals

Wendland

Schmitt

Zimmermann

et al. 2023

Informatics in Medicine Unlocked

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Section: Discussionmentioning

confidence: 99%

Machine learning models for predicting severe COVID-19 outcomes in hospitals

Wendland

Schmitt

Zimmermann

et al. 2023

Informatics in Medicine Unlocked

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“…Increased expression of ALOX5AP, ALOX5, and plasma LTB 4 are also noted in diabetic COVID-19 cases requiring intensive care [65]. G Protein-Coupled Receptor Class C Group 5 Member C (GPRC5C) whose structural variants have been associated with poor prognosis in COVID-19 [66]. Mitogen-activated Protein Kinase 7 (MAP2K7) encodes for an augmenter of the c-Jun kinase pathway during T-cell activation and is elevated in severe COVID-19 [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

Exome-Wide Association Study Reveals Host Genetic Variants Likely Associated with the Severity of COVID-19 in Patients of European Ancestry

Upadhyai

Shenoy

Banjan

et al. 2022

Life

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Host genetic variability plays a pivotal role in modulating COVID-19 clinical outcomes. Despite the functional relevance of protein-coding regions, rare variants located here are less likely to completely explain the considerable numbers of acutely affected COVID-19 patients worldwide. Using an exome-wide association approach, with individuals of European descent, we sought to identify common coding variants linked with variation in COVID-19 severity. Herein, cohort 1 compared non-hospitalized (controls) and hospitalized (cases) individuals, and in cohort 2, hospitalized subjects requiring respiratory support (cases) were compared to those not requiring it (controls). 229 and 111 variants differed significantly between cases and controls in cohorts 1 and 2, respectively. This included FBXO34, CNTN2, and TMCC2 previously linked with COVID-19 severity using association studies. Overall, we report SNPs in 26 known and 12 novel candidate genes with strong molecular evidence implicating them in the pathophysiology of life-threatening COVID-19 and post-recovery sequelae. Of these few notable known genes include, HLA-DQB1, AHSG, ALOX5AP, MUC5AC, SMPD1, SPG7, SPEG,GAS6, and SERPINA12. These results enhance our understanding of the pathomechanisms underlying the COVID-19 clinical spectrum and may be exploited to prioritize biomarkers for predicting disease severity, as well as to improve treatment strategies in individuals of European ancestry.

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“…There is no question that TGPs continue to remain relevant to IEI diagnostics, but this also means tackling the associated questions of panel content revision and re-analysiswhat should be the criteria for gene inclusion and exclusion, how frequently should revision and re-analysis occur, and who will be responsible? Emerging genomics platforms now offer the promise of identifying previously elusive IEI genetic lesions [144][145][146], but also demand the development of novel bioinformatics pipelines, data infrastructures, and analytical strategies. All of these considerations highlight the urgent need for flexible, evolving and realistic demographic-appropriate guidelines, as well as acknowledging and addressing the systemic biases currently found in our data [147].…”

Section: Many Of Our Index Patients Did Not Present With the Most 'Ca...mentioning

confidence: 99%

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

Peng

Al-Ddafari²,

Caballero-Oteyza³

et al. 2023

Preprint

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The advent of next-generation sequencing (NGS) technologies has greatly expanded our understanding of both the clinical spectra and genetic landscape of inborn errors of immunity (IEIs). As history has shown and recent large-scale studies of monogenic risk for severe COVID have confirmed, endogamous populations may be enriched for unique, ancestry-specific disease-causing variants as a consequence of geography and/or culture. From a diagnostic perspective, this consideration may significantly impact molecular testing and analysis strategies. Herein, we report on the diagnostic yield of a 2-step NGS-based testing approach beginning with targeted gene panels (TGPs) and reflexing to whole exome sequencing (WES) if negative for Northwest Algerian patients with suspected IEIs. A total of fourteen families were screened using TGPs tailored to their IEI subtypes of common variable immunodeficiency (CVID), inflammatory bowel disease (IBD) or chronic mucocutaneous candidiasis (CMC)-hyperIgE syndrome (HIES), resulting in a total of four definitive or highly likely molecular diagnoses (29% yield). Subsequent application of WES to eight of the ten remaining unsolved cases yielded an additional four diagnoses, giving a 57% overall yield. At least two additional individuals were found to harbor suggestive candidate variants on exome warranting further investigation, while others carried candidate variants or known risk alleles likely contributing to their clinical findings. Only in one patient’s case did we fail to identify any viable potential candidates. By achieving diagnostic yields comparable to those currently quoted for application of short-read NGS to IEI detection, our study demonstrates the viability of a 2-step NGS-based testing strategy in a selected endogamous population. Data from our localized cohort also showed some similarities and differences from NGS studies performed on larger regional IEI cohorts. Finally, our results also highlight many short-comings currently inherent to the application of genomics for clinical IEI diagnostics. Not only does the global community need to address ongoing inequities in representation, access, and infrastructure, but the ability to obtain precise and detailed clinical data remains paramount for achieving diagnostic certainty in the face of complex genotype-phenotype relationships.

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Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

Cited by 17 publications

References 81 publications

Machine learning models for predicting severe COVID-19 outcomes in hospitals

Machine learning models for predicting severe COVID-19 outcomes in hospitals

Exome-Wide Association Study Reveals Host Genetic Variants Likely Associated with the Severity of COVID-19 in Patients of European Ancestry

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

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