A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

Presence of rare potential pathogenic variants in subjects under 60 years old with very severe or fatal COVID-19

Background/Objectives: Genetic variants affecting host defense against pathogens may help explain COVID-19 fatal outcomes. Our aim was to identify rare genetic variants related to COVID-19 severity in a selected group of patients under 60 years who required intubation or resulting in death. Method(s): Forty-four very severe COVID-19 patients were selected from the Spanish STOP-Coronavirus cohort, which comprises more than 3,500 COVID-19 patients. Genotype was performed by whole exome sequencing and variants were selected by using a gene panel of 867 candidate genes (immune response, primary immunodeficiencies or coagulation, among other). Variants were filtered, priorized and their potential pathogenicity was assessed following ACGM criteria. Result(s): We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic (26%). Mostly, the candidate variants were located in genes related to immune response (38%), congenital disorders of glycosylation (14%) or damaged DNA binding genes (9%). A network analysis, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks enriched in carbohydrate metabolism and in DNA metabolism and repair processes. Conclusion(s): The variants identified affect different, but interrelated, functional pathways such as immune response and glycosylation. Further studies are needed for confirming the ultimate role of the new candidate genes described in the present study on COVID-19 severity.

COVID-19: How to analyze data from whole-exome sequencing?

Background/Objectives: COVID-19 can affect anyone with the disease's symptoms ranging from mild to very severe. Although environmental, clinical, and social factors play an important role in the disease process, host genetic factors are not negligible either. In the present article, we attempted to elaborate on the spectrum of risk variants and genes identified in different ways and their possible relationship to COVID-19 severity and/or mortality. Method(s): We present three different approaches to search host genetic risk factors that influence the development of COVID-19 disease. First, we analyzed the exome sequencing data obtained from Slovak patients who died of COVID-19. Second, we selected risk factors/genes that were associated with COVID-19. Finally, we compared each group of found risk variants with data from dead patients and two control groups, worldwide public data of the Non-Finnish European population from the gnomAD database, and genetic data from Non-invasive prenatal testing in the Slovak population. Result(s): We illustrate the utility of genomic data showed strong association in meta-analyses conducted by the COVID-19 HGI Browser. Conclusion(s): To our knowledge, the present study is the first population analysis of COVID-19 variants worldwide and also in the Slovak population that provides different approaches to the analysis of genetic variants in whole-exome sequencing data from patients who have died of COVID-19.

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals

Background/Objectives: Emerging evidence suggests that complement system infection-dependent hyperactivation may worsen COVID-19 outcome. We investigated the role of predicted high impact variants -referred as Qualifying Variants (QVs) -of complement system genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. Method(s): Exploiting Whole-Exome Sequencing (WES) data and 56 complement system genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (age >= 60 y.o.) and 56,885 European individuals from the gnomAD database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized COVID-19 patients. Result(s): We found an enrichment of QVs in three genes (MASP1, COLEC10 and COLEC11), which belong to the lectin pathway, in the asymptomatic cohort. Moreover, individuals with QVs showed lower serum levels of Masp1 and of prothrombin activity compared to controls while no differences were observed for CH50 and AH50 levels that measure the activity of classical and alternative complement pathways, respectively. Finally, integrative analyses of genome-wide association study and expression quantitative loci traits data showed a correlation between polymorphisms associated with asymptomatic COVID-19 and decreased expression of MASP1, COLEC11 and COLEC10 genes in lung tissue. Conclusion(s): This study suggests that rare genetic variants can protect from severe COVID-19 by mitigating the activation of lectin pathway and prothrombin activity.

Identification of genetic determinants of COVID-19 severity by exome sequencing

Background/Objectives: The severity of the symptoms of coronavirus disease 2019 (COVID-19) has been associated to age, comorbidity, and male sex. Besides virus characteristics, host genetic factors influence the infection outcome. Different genome-wide association studies and meta-analyses investigated the contribution of common variants, whereas the role of rare variants just started to be elucidated. Our goal is to determine the contribution of rare variants to the development of severe COVID-19 in the Italian population. Method(s): We compared the genetic background of 215 severe COVID-19 patients with 1764 individuals from the general population. Rare variants (minor allele frequency <1%) from wholeexome sequencing data were retrieved using a bioinformatics variant discovery pipeline. We tested the impact of rare variants (classified according to their predicted effect on the gene product) both using a burden test design, and an iterative machine learning (ML) approach. Result(s): We identified a total of 690,000 rare variants in the entire examined population. Among them, 250 were associated with COVID-19 severity at a nominal P < 0.05. Gene-based burden test revealed a gene with an excess of loss-of-function mutations at P < 0.05. Finally, the ML approach, analysing all the 690,000 rare variants, identified the best combination of variants that is able to predict COVID-19 severity in our cohort. Conclusion(s): Our work provides new insights on the genetic signature of COVID-19 in the Italian population. The most informative rare variants could be exploited to define individuals' risk profiles to COVID-19 severity for the Italian population.

Fatal COVID-19 in an infant prompted an early diagnosis of ZNFX1 deficiency in a sibling

Background: NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1 deficiency in humans is very rare;to date, only fifteen cases have been reported by Vavassori S et al. (10.1016/j.jaci.2021.03.045). The disease presented in all cases as severe viral infections complicated by multisystem inflammation evolved to multiorgan failure with a high mortality rate. Pediatric Allergy and Immunology Section at Queen Rania Children's Hospital in Jordan had confirmed the diagnosis of ZNFX1 deficiency in an infant at his first presentation with severe viral illness based on the positive family history of one sibling death caused by complicated COVID-19 infection. Case presentation: A 12-month-old boy was born to consanguineous parents, full-term, with no NICU admission. He was doing well till the age of four months when he was admitted to the hospital with fever, hypoactivity, and maculopapular skin rash. On admission, he was ill, hypoactive, and febrile, and a physical exam showed hepatosplenomegaly and maculopapular skin rash. His lab showed thrombocytopenia, elevated transaminases, hyperferritinemia, and high CRP;he was treated with broad-spectrum antibiotics, but he continued to deteriorate, and his infectious workup was unrevealing, including COVID-19 PCR. His older sibling died at eight months in 2020 when she got a COVID-19 infection, deceased after rapid deterioration evolved to multiorgan failure. Unfortunately, she had no stored DNA, as she was treated at a peripheral hospital. Based on this presentation and the fatal COVID-19 infection, pediatric immunology service got consulted;we did an immunological workup, which showed normal lymphocyte subsets, Immunoglobulins, and bacterial antibodies. Whole exome sequencing showed a homozygous frameshift mutation in the ZNFX1 gene, protein change defect had detected;p.Tyr555MetfsTer6, and nucleotide change variant: c.1663_1665delTACinsAT. Family screening showed heterozygous for the same variant in both parents and a healthy sibling. The patient was diagnosed with the hemophagocytic lymphohistiocytosis-like disease and treated with steroids, intravenous immunoglobulin, and antimicrobials, he showed complete recovery, and we are going to do bone marrow transplantation as his brother is 8/8 HLA matched.Copyright © 2023 Elsevier Inc.

Ndegree39 - Fulminant life-threatening myopathy of the genetic origin

Objectives: Acute myopathy are seen in critically ill patients, in severe SARS-CoV2 pneumonia requiring mechanical ventilation, and other infection illness, toxin and drug-induced complications, or systemic inflammation. Periodic paralysis or carnitine disorders are known genetic causes of acute muscular weakness, besides genetically determined muscle diseases rarely have an acute clinical course. Content: Case presentation: 61-years old, healthy woman, after a one-time vaccination against Covid-19 about 2 weeks earlier, was admitted to the Neurological Department due to symptoms lasting for 2 days. On the first day of the disease she complained of vertigo and double vision, on the following day dysarthia and dysphagia appeared, she stopped walking. On the second day of hospitalization, the patient required mechanical ventilation. The initial diagnosis of Guillaine-Barre syndrome was not confirmed in the electrophysiological and laboratory (CSF) studies. Myopathic pattern with polyphasic potentials of short duration and low amplitude was observed in EMG, without spontaneous activity. In the electron microscope numerous fat drops between bundles of myofibrils in most muscle fibers were seen. She received intravenous immunoglobulins, and steroid therapy, together with high doses of vitamin B2 with very good motor improvement. Multiple acyl-CoA dehydrogenase deficiency (MADD) was suspected, and the Whole Exome Sequencing (WES) was performed. Conclusion(s): The authors note the possibility of acute, life-threatening myopathy, which may be caused by a genetic defect. MADD is a very rare genetic entity which can manifest for the first time very suddenly, especially in the presence of triggers, including but not limited to after vaccinations. Keywords: Acute myopathy;Multiple acyl-CoA dehydrogenase deficiency;Vitamin B2.Copyright © 2023

28th Italian Melanoma Intergroup National Congress

The proceedings contain 35 papers. The topics discussed include: germline variants and prognostic factors for cutaneous melanoma in children and adolescents;association between polygenic risk score and multiple primary melanoma;Porocarcinoma: an epidemiological, clinical, and dermoscopic 20-year study;primary cutaneous melanoma and COVID-19: a hospital-based study;atypical spitz tumors: an epidemiological, clinical and dermoscopic multicenter study with 16 years of follow-up;pediatric melanoma: an epidemiological, clinical and dermoscopic multicenter study;recurrence-free survival prediction in melanoma patients by exploiting artificial intelligence techniques on melanoma whole slide images;ultra-high frequency ultrasound and machine learning approaches for the differential diagnosis of melanocytic lesions;and genetic determinants of response to therapy in a real-world setting of advanced/metastatic melanoma patients: whole-exome sequencing and CFDNA analysis.

Activity of Cefiderocol and Other New Antibiotics Against Extensively Drug-Resistant Klebsiella pneumoniae Strains.

Background. The spread of extensive drug-resistance among gram-negative bacteria calls for the search for antimicrobics with new mechanisms of actions. The aim was to assess susceptibility of extensively drug-resistant K.pneumoniae strains to cefiderocol and other new inhibitor-protected beta-lactams, and to determine genetic mechanisms of antibiotic resistance. Methods. This study included 30 extensively drug-resistant K.pneumoniae strains collected in 2016-2021 from 4 regions of Belarus. Carbapenemase genes were detected by real-time PCR. Minimum inhibitory concentrations (MICs) for cefiderocol and other new antibiotics were assessed by microdilution method using the Sensititre system. Whole genome sequencing was performed for 2 resistant and 3 cefiderocol-susceptible strains. Genome assemblies and annotation were performed using UGENE v. 37.0 software. Nucleotide sequences were translated using CLC Sequence Viewer v. 8.0 (QIAGEN) package. The PROVEAN software was used to assess amino asides substitutions and their influence on the functional activity of proteins. Results. KPC carbapenemase-producers were 4 strains, OXA-48 - 17, KPC+OXA-48 - 1, NDM - 7, OXA-48 + NDM - 1. All KPC-producers were susceptible to imipenem/relebactam and meropenem/vaborbactam. Resistance to ceftazidime-avibactam was noted in all NDM producers and OXA-48+NDM co-producer. The study has identified 9 cefiderocol-resistant strains. These were NDM and OXA-48-producers isolated from hospitalized patients with COVID-19 infection from 3 regions of Belarus. Resistant strains had functionally significant nonsynonymous substitutions in the genes of TonB-dependent receptors for catecholate siderophores FepA (F472V, P64S) and Fiu (T92S). Conclusion. The study has shown high efficacy of new inhibitor-protected carbapenems and cephalosporins against certain types of carbapenemase-producers. Strains with mutational resistance to cefiderocol, an antibiotic not previously used in Belarus, have been identified.Copyright © Team of Authors, 2022.

Emergence of BA.4/BA.5 Omicron Sub-lineages and Increased SARS-CoV-2 Incidence in Senegal

Background: The Omicron variant B.1.1.529 has led to a new dynamic in the COVID-19 pan-demic, with an increase in cases worldwide. Its rapid propagation favors the emergence of novel sub-lineages, including BA.4 and BA.5. The latter has shown increased transmissibility compared to other Omicron sub-lineages. In Senegal, the emergence of the Omicron variant in December 2021 characterized the triggering of a short and dense epidemiological wave that peaked at the end of February. This wave was followed by a period with a significant drop in the number of COVID-19 cases, but an upsurge in SARS-CoV-2 infection has been noted since mid-June. Objective(s): The purpose of this brief report is to give an update regarding the genomic situation of SARS-CoV-2 in Dakar during this phase of recrudescence of cases. Method(s): We performed amplicon-based SARS-CoV-2 sequencing on nasopharyngeal swab samples from declared COVID-19 patients and outbound travelers that tested positive. Result(s): Ongoing genomic surveillance activities showed that more than half of recent COVID-19 cases were due to the BA.4 and BA.5 sub-lineages that share two critical mutations associated with increased transmissibility and immune response escape. The circulation of recombinants between Omicron sub-lineages was also noted. Conclusion(s): Despite the lack of proven severity of BA.4 and BA.5 sub-lineages, their increased transmis-sibility causes a rapid spread of the virus, hence a surge in the number of cases. This rapid spread consti-tutes a greater risk of exposure for vulnerable patients. To tackle this issue, any increase in the number of cases must be monitored to support public health stakeholders. Therefore, genomic surveillance is an ever-essential element in managing this pandemic.Copyright © 2022 Bentham Science Publishers.

Evaluation and limitations of different approaches among COVID-19 fatal cases using whole-exome sequencing data.

BACKGROUND: COVID-19 caused by the SARS-CoV-2 infection may result in various disease symptoms and severity, ranging from asymptomatic, through mildly symptomatic, up to very severe and even fatal cases. Although environmental, clinical, and social factors play important roles in both susceptibility to the SARS-CoV-2 infection and progress of COVID-19 disease, it is becoming evident that both pathogen and host genetic factors are important too. In this study, we report findings from whole-exome sequencing (WES) of 27 individuals who died due to COVID-19, especially focusing on frequencies of DNA variants in genes previously associated with the SARS-CoV-2 infection and the severity of COVID-19. RESULTS: We selected the risk DNA variants/alleles or target genes using four different approaches: 1) aggregated GWAS results from the GWAS Catalog; 2) selected publications from PubMed; 3) the aggregated results of the Host Genetics Initiative database; and 4) a commercial DNA variant annotation/interpretation tool providing its own knowledgebase. We divided these variants/genes into those reported to influence the susceptibility to the SARS-CoV-2 infection and those influencing the severity of COVID-19. Based on the above, we compared the frequencies of alleles found in the fatal COVID-19 cases to the frequencies identified in two population control datasets (non-Finnish European population from the gnomAD database and genomic frequencies specific for the Slovak population from our own database). When compared to both control population datasets, our analyses indicated a trend of higher frequencies of severe COVID-19 associated risk alleles among fatal COVID-19 cases. This trend reached statistical significance specifically when using the HGI-derived variant list. We also analysed other approaches to WES data evaluation, demonstrating its utility as well as limitations. CONCLUSIONS: Although our results proved the likely involvement of host genetic factors pointed out by previous studies looking into severity of COVID-19 disease, careful considerations of the molecular-testing strategies and the evaluated genomic positions may have a strong impact on the utility of genomic testing.

Whole exome sequencing identifies a rare variant in MAS1 gene in a subject with lethal COVID-19.

COVID-19 may be considered a multifactorial disease caused by the interaction between the virus itself, as the environmental contribute, and the genetic background of the host. SARS-CoV-2 infection occurs through the interaction between the spike protein and ACE2, a receptor in the host cells. Clinically, COVID-19 is characterized by a high heterogeneity in symptomatology ranging from asymptomatic to severe symptoms, and even worsening to death. This variability relies on the host genomic profile and other individual comorbidities. We performed exome analysis in one family displaying a variable spectrum of SARS-CoV-2 infection despite a common exposure. After segregation analysis, we found that the c.446C>T p.(S149L) in MAS1 gene was exclusively present in the individual with severe COVID-19, who died because of pneumonia and multiple thrombotic events. MAS1 encodes a receptor for Ang1-7 in the renin-angiotensin system (RAS) with an anti-inflammatory, anti-fibrotic and anti-angiogenic effect. We hypothesize that downregulation of RAS, due to this rare variant, might impair the protective effect and concur to the clinical severity of the disease. Our results support the protective role of the ACE2/Ang-(1-7)/Mas1 axis and the potential danger of its dysregulation leading to severe COVID-19 disease; if further confirmed, these findings will be useful for management of critically ill patients.

Host Genetic Risk Factors Associated with COVID-19 Susceptibility and Severity in Vietnamese.

Since the emergence and rapid transmission of SARS-CoV-2, numerous scientific reports have searched for the association of host genetic variants with COVID-19, but the data are mostly acquired from Europe. In the current work, we explored the link between host genes (SARS-CoV-2 entry and immune system related to COVID-19 sensitivity/severity) and ABO blood types with COVID-19 from whole-exome data of 200 COVID-19 patients and 100 controls in Vietnam. The O blood type was found to be a protective factor that weakens the worst outcomes of infected individuals. For SARS-CoV-2 susceptibility, rs2229207 (TC genotype, allele C) and rs17860118 (allele T) of IFNAR2 increased the risk of infection, but rs139940581 (CT genotype, allele T) of SLC6A20 reduced virus sensitivity. For COVID-19 progress, the frequencies of rs4622692 (TG genotype) and rs1048610 (TC genotype) of ADAM17 were significantly higher in the moderate group than in the severe/fatal group. The variant rs12329760 (AA genotype) of TMPRSS2 was significantly associated with asymptomatic/mild symptoms. Additionally, rs2304255 (CT genotype, allele T) of TYK2 and rs2277735 (AG genotype) of DPP9 were associated with severe/fatal outcomes. Studies on different populations will give better insights into the pathogenesis, which is ethnic-dependent, and thus decipher the genetic factor's contribution to mechanisms that predispose people to being more vulnerable to COVID-19.

Multiomics analysis of male infertility†.

Infertility affects 8-12% of couples globally, and the male factor is a primary cause in ~50% of couples. Male infertility is a multifactorial reproductive disorder, which can be caused by paracrine and autocrine factors, hormones, genes, and epigenetic changes. Recent studies in rodents and most notably in humans using multiomics approach have yielded important insights into understanding the biology of spermatogenesis. Nonetheless, the etiology and pathogenesis of male infertility are still largely unknown. In this review, we summarized and critically evaluated findings based on the use of advanced technologies to compare normal and obstructive azoospermic versus nonobstructive azoospermic men, including whole-genome bisulfite sequencing, single-cell RNA-seq, whole-exome sequencing, and transposase-accessible chromatin using sequencing. It is obvious that the multiomics approach is the method of choice for basic research and clinical studies including clinical diagnosis of male infertility.

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman-Diamond Syndrome.

Background: Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive ribosomopathy mainly characterized by exocrine pancreatic insufficiency, skeletal alterations, neutropenia, and a relevant risk of hematological transformation. At least 90% of SDS patients have pathogenic variants in SBDS, the first gene associated with the disease with very low allelic heterogeneity; three variants, derived from events of genetic conversion between SBDS and its pseudogene, SBDSP1, provided the alleles observed in about 62% of SDS patients. Methods: We performed a reanalysis of the available WES files of a group of SDS patients with biallelic SBDS pathogenic variants, studying the results by next bioinformatic and protein structural analysis. Parallelly, careful clinical attention was given to the patient focused in this study. Results: We found and confirmed in one SDS patient a germline heterozygous missense variant (c.100T>C; p.Phe34Leu) in the EIF6 gene. This variant, inherited from his mother, has a very low frequency, and it is predicted as pathogenic, according to several in silico prediction tools. The protein structural analysis also envisages the variant could reduce the binding to the nascent 60S ribosomal. Conclusion: This study focused on the hypothesis that the EIF6 germline variant mimics the effect of somatic deletions of chromosome 20, always including the locus of this gene, and similarly may rescue the ribosomal stress and ribosomal dysfunction due to SBDS mutations. It is likely that this rescue may contribute to the stable and not severe hematological status of the proband, but a definite answer on the role of this EIF6 variant can be obtained only by adding a functional layer of evidence. In the future, these results are likely to be useful for selected cases in personalized medicine and therapy.

Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities.

A dilated lateral ventricle is a relatively common finding on prenatal ultrasound, and the causes are complex. We aimed to explore the etiology of a fetus with a dilated lateral ventricle. Trio whole-exome sequencing was performed to detect causative variants. A de novo variant of TAOK1 (NM_020791.2: c.227A>G) was detected in the proband and evaluated for potential functional impacts using a variety of prediction tools. Droplet digital polymerase chain reaction was used to exclude the parental mosaicism and to verify the phasing of the de novo variant. Based on peripheral blood analysis, the parents did not exhibit mosaicism at this site, and the de novo variant was paternally derived. Here, we describe a fetus with a de novo likely pathogenic variant of TAOK1 who had a dilated lateral ventricle and a series of particular phenotypes. This case expands the clinical spectrum of TAOK1-associated disorders. We propose a method for solving genetic disorders in which the responsible genes have not yet gone through ClinGen curation, particularly for prenatal cases.

Recurrent, non-traumatic, non-exertional rhabdomyolysis after immunologic stimuli in a healthy adolescent female: a case report.

BACKGROUND: Dysferlinopathy refers to a heterogenous group of autosomal recessive disorders that affect a skeletal muscle protein called dysferlin. These mutations are associated with limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, asymptomatic hyperCKemia, and distal myopathy with anterior tibial onset. CASE PRESENTATION: A 16 year old female presented with myalgia, weakness and dark urine one week after her second BNT162b2 mRNA (Pfizer) vaccine. Initial serum creatine kinase (CK) was measured at 153,000 IU/L, eventually up-trending to over 200,000 IU/L. However, stable renal function precluded hemodialysis allowing discharge after 10 days of intravenous (IV) hydration and alkaline diuresis. Just two years prior to the current presentation, the patient was hospitalized following Group A Streptococcal pharyngitis infection complicated by rhabdomyolysis. She presented with fatigue, lower extremity weakness, and dark oliguria with CK measuring 984,800 IU/L. IV hydration was attempted however hemodialysis was ultimately required throughout her 24-day hospital stay. Her episode was presumed to be idiopathic and no further work-up was performed at that time. During the patient's current hospitalization, she reported similar symptomology (myalgias and weakness) following her first quadrivalent Gardasil vaccine at age 11. No hospitalization was required at that time. A comprehensive workup was now initiated while the patient was being treated for her suspected second or third non-exertional, non-traumatic rhabdomyolysis. Rheumatologic, metabolic, infectious, and endocrinologic workup were all unremarkable. Patient eventually had whole exome sequencing performed which revealed a heterozygous pathogenic variant in the DYSF gene (DYSF c.2643 + 1G > A) encoding dysferlin. No clinically significant sequelae occurred thus far. CONCLUSIONS: While there have been reports of symptomatic heterozygote carriers of dysferlinopathies, to our knowledge none have been associated with recurrent rhabdomyolysis after immunogenic stimuli. This unique case presentation highlights the importance of a multi-disciplinary care team, the utility of modern whole-exome gene sequencing, and the future challenges of balancing vaccine risk vs benefit.

Human interaction targets of SARS-COV-2 spike protein: A systematic review

Objectives: The development of effective targeted therapy and drug-design approaches against the SARS-CoV-2 is a universal health priority. Therefore, it is important to assess possible therapeutic strategies against SARS-CoV-2 via its most interaction targets. The present study aimed to perform a systematic review on clinical and experimental investigations regarding SARS-COV-2 interaction targets for human cell entry. Methods: A systematic search using relevant MeSH terms and keywords was performed in PubMed, Scopus, Embase, and Web of Science (ISI) databases up to July 2021. Two reviewers independently assessed the eligibility of the studies, extracted the data, and evaluated the methodological quality of the included studies. Additionally, a narrative synthesis was done as a qualitative method for data gathering and synthesis of each outcome measure. Results: A total of 5610 studies were identified, and 128 articles were included in the systematic review. Based on the results, spike antigen was the only interaction protein from SARS-CoV-2. However, the interaction proteins from humans varied including different spike receptors and several cleavage enzymes. The most common interactions of the spike protein of SARS-CoV-2 for cell entry were ACE2 (entry receptor) and TMPRSS2 (for spike priming). A lot of published studies have mainly focused on the ACE2 receptor followed by the TMPRSS family and furin. Based on the results, ACE2 polymorphisms as well as spike RBD mutations affected the SARS-CoV-2 binding affinity. Conclusion: The included studies shed more light on SARS-CoV-2 cellular entry mechanisms and detailed interactions, which could enhance the understanding of SARS-CoV-2 pathogenesis and the development of new and comprehensive therapeutic approaches.