Complete response to eculizumab in atypical hemolytic uremic syndrome with homozygous C3 mutation

Case Report: Atypical Hemolytic Uremic Syndrome (atypical HUS) is a rare and severe form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, intravascular hemolysis, and acute kidney injury with an incidence of 1 per million.1 Dysregulation and overactivation of the complement alternative pathway due to genetic mutations have been detected in 40-60% of patients with sporadic or familial atypical HUS.2,4 Triggers include viral illness, pregnancy, malignancy, sepsis, or sporadically with no known inciting event.1 Atypical HUS is a severe disease with a 2-10% risk of mortality, 33% risk of end-stage renal failure, and 50% chance of relapse.5 A 24-year-old female with prior history of atypical HUS at the age of 16 (with response to plasmapheresis) presented to the ER with a 5-day history of fever, chills, sore throat, nausea, vomiting, and dark urine. She tested positive for COVID-19. The exam revealed scleral icterus and scattered petechiae. Labs demonstrated nadir hemoglobin (Hgb) of 9.2 g/dL, platelet count of 52 000k/uL, haptoglobin < 30 mg/dL, peak LDH 1128U/L and creatinine 4.62 mg/dL. Urinalysis is consistent with hemoglobinuria. Schistocytes were noted on the peripheral smear. Rapid streptococcal antigen test and C3, C4, and IgA levels were unremarkable. Chest X-Ray, X-ray KUB, and ultrasound abdomen were unremarkable. The pregnancy test was negative. ADAMTS13 was >100%. Genetic analysis after the initial episode at age 16 revealed autosomal recessive inheritance c.193A > c gene mutations in C3. The patient received IV fluids, ceftriaxone for cystitis, and two units of Fresh Frozen Plasma. She initiated treatment with eculizumab. She also received the MENVEO and meningitis B vaccine per protocol due to the risk of meningitis from terminal complement deficiencies. After 4 infusions of eculizumab, patient's labs improved to platelet count of 307 000 k/uL, Hgb 12.2 g/ dL (nadir 9.2 g/dL), haptoglobin 78 mg/dL normalization of LDH and improved creatinine. Atypical HUS is a rare form of TMAwith mutations in C3 noted in 5% of cases. Complement cascade dysfunction leads to endothelial deposits and microvasculature damage. The resulting prothrombotic state causes obstructive microvascular thrombi predominantly affecting the kidneys but can cause multiorgan dysfunction. The SARS-CoV-2 virus may precipitate atypical HUS relapse due to endothelial damage and complement activation further intensified in patients with existing complement aberrations. Plasma exchange remains a standard of care for atypical HUS, as it effectively removes the antibodies and other proteins. Eculizumab a humanized monoclonal IgG antibody binds to complement proteins, preventing cleavage into C5a and C5b blocking C5b-9(MAC) activation. In patients with CFH, CFI, C3, and CFB mutations, eculizumab is the preferred intervention. Copyright © 2023 Southern Society for Clinical Investigation.

Homozygous-Recessive Characteristics as a Biomarker of Predisposition for COVID-19.

Coronavirus disease (COVID-19), a new form of severe acute respiratory syndrome, has caused a global pandemic. The aim of this study was to analyze homozygous-recessive characteristics (HRC) in the group of COVID-19 patients, considering their gender, forms of the disease (mild and severe symptoms), risk factors: hypertension, diabetes mellitus type 2, hyperlipidemia, smoking habits, and the distribution of ABO blood group. Using the HRC test, we analyzed 20 HRCs in a sample of 321 individuals: 205 patients and 116 controls. The average HRC in patients was significantly higher than controls, as well as in patients with severe symptoms compared to patients with mild symptoms. The patients with higher HRC (cut-off ≤5.5) experienced a significantly increased risk of disease of 2.3 times (OR = 2.315, p < .0005). Our results indicate that the HRC test could be used as a screening in recognizing predisposition for COVID-19.

ACUTE HEPATIC SEQUESTRATION CRISIS: AN OFTEN UNDERDIAGNOSED AND FATAL SYNDROME

SESSION TITLE: Critical Renal and Endocrine Disorders Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Sickle Cell Disease (SCD) is an autosomal recessive disease characterized by an abnormal beta-globin chain of hemoglobin (Hb) that leads to malformed sickled cells with a multitude of downstream microvascular occlusions and anemia. While splenic infarction is by far the most common gastrointestinal (GI) manifestation, vaso-occlusion may occur in the liver, leading to an acute hepatic crisis. Acute hepatic sequestration of sickled erythrocytes is an exceedingly rare manifestation. CASE PRESENTATION: A 43-year-old man with homozygous sickle cell disease complicated by End-Stage renal disease was admitted with generalized malaise, right upper quadrant (RUQ) abdominal pain, nausea and vomiting. He was febrile with a temperature of 38.1°C, hypotensive with a blood pressure of 93/61 mmHg and tachycardic with a heart rate of 120 bpm. He was lethargic and uncomfortable with diffuse abdominal tenderness without guarding. Due to concern for septic shock, blood cultures, COVID PCR and influenza were obtained, and the patient was rapidly transferred to the intensive care unit for closer monitoring. Empiric vancomycin and cefepime were started promptly. The initial hemoglobin level was 6.1mg/dL with a leukocytosis of 31.2 K/CUMM and absolute neutrophil count of 21.8 K/CUMM;total hyperbilirubinemia of 17.45 mg/dL, direct hyperbilirubinemia of 11.46mg/dL and elevated INR at 1.66. Computed tomography of the abdomen and pelvis without contrast showed a known 4 cm cystic lesion of the right hepatic lobe and atrophic kidneys. Duplex flow of the abdomen and pelvis showed no portal vein thrombosis and patent flow in the portal vein and artery. Over the course of several hours, the patient's hemoglobin dropped to 3.8mg/dL with a steep rise in LDH and total bilirubin to 632 U/L and 27.04 mg/dL, respectively consistent with hepatic sequestration crisis. Patient was transfused with two units of packed red blood cells, fluid hydration and initiation of erythrocyte exchange transfusion. Prior to receiving exchange transfusion, the patient experienced rapid clinical deterioration with subsequent pulseless electrical activity. Return of spontaneous circulation was achieved transiently however patient's family at this point opted for palliative measures and the patient passed away shortly thereafter. DISCUSSION: Complications of SCD manifest in multiple organ systems. One of the few acute manifestations, hepatic sequestration crisis, is often unfamiliar to many clinicians and left unrecognized, results in poor clinical outcomes. It is rarely encountered and treatment options with blood and, more importantly, exchange transfusion remains often underutilized. CONCLUSIONS: Acute hepatic sequestration crisis is an often-unrecognized manifestation of SCD in which delay in diagnosis and prompt treatment with exchange and blood transfusions may impart a significant risk of mortality in an already prone patient population. Reference #1: Shah R, Taborda C, Chawla S. Acute and chronic hepatobiliary manifestations of sickle cell disease: a review World J Gastrointestinal Pathophysiology 2017;8(3): 108-116 Reference #2: Norris W. Acute hepatic sequestration in sickle cell disease. J of the National Medical Association 2004;96: 1235-1239 Reference #3: Praharaj D, Anand A. Sickle Hepatopathy J of Clinical and Experimental Hepatology 2021;11: 82-96 DISCLOSURES: No relevant relationships by Karim Dirani No relevant relationships by Georgiana Marusca No relevant relationships by Aryan Shiari

eP520: Screening results in 186 any-health-status adults in primary care clinics receiving clinical NGS for 431 health risk and recessive genes

Introduction: The ACMG has recommended returning clinically relevant results for certain genes when identified in research or as secondary findings in diagnostic testing. Research studies have shown that genomic population screening detects patients with previously unrecognized and often actionable health risks or genetic conditions, with acceptably low levels of harm. Cascade testing of relatives at risk is enabled. Screening for recessive disorder carrier status with gene sequencing panels is common in clinical practice. Preventative screenings routinely occur in primary care settings. The cost of reliably sequencing of many genes in a clinically reliable fashion is approaching levels where offering genomic screening tests may be contemplated for entire populations, and the results used for preventative health purposes, including clinical correlation, early screening, and education. In anticipation of universal genome sequence-based screening, integrated with existing health risk screenings, we piloted a novel implementation of clinical genomic population screening in primary care, mostly family medicine clinics. Screening involved clinical sequencing and reporting of 431 genes where variants are associated with personal health risks or recessive disease carrier status. Methods: Interested primary care providers (PCPs) in two Family Medicine practice systems were invited to participate and given onboarding education. Adult patients with any health status were introduced to The Genomic DNA Test and provided test information by their PCPs in the context of preventative health assessment. Patient education materials included paper, online, and video information, a ‘hotline,’ and optional free genetic counseling. Patients completing a bespoke, health system-approved, written clinical consent provided blood or occasionally saliva samples that were NGS sequenced according to validated procedures in a commercial CLIA-certified genetic testing laboratory. Laboratory reports were returned to the PCP and patient after a local genetics professional added a 1-to-3-page messaging document, the Genomic Medicine Action Plan (GMAP). The PDF-format reports and GMAP were placed in the patient’s electronic health record. Only pathogenic (P) and likely pathogenic (LP) variants were reported. Variant classification was according to Sherloc, the performing laboratory’s system. Patients or providers could request free post-test genetic counseling locally, and the performing lab offered free family member testing and limited-cost partner testing for health risk panel genes and recessive disorder panel genes, respectively. Patients with health risk results were defined as being heterozygous for a P/LP variant for a dominant condition or for a recessive condition where some heterozygotes are symptomatic or co-dominant, hemizygous for a P/LP variant for an X-linked recessive condition, or bi-allelic and plausibly in trans for an autosomal (or X-linked in a female) recessive condition. Many such conditions that are common have reduced or low penetrance, and were characterized as increased risk compared to those not having those variants. When increased risk was identified, the GMAP recommended appropriate medical responses and/or patient education. As part of quality assessment of the pilot, the frequencies of reported results and certain events are monitored. Results: Between November 2019 and October 2021, 186 patients with a median age of 58 years were tested by 20 PCPs at no cost to patients or insurance. Testing volumes declined during the COVID-19 pandemic and when other health system events made high demands on PCPs and their staff. Only 13.3% of patients had no reportable variants in any of the 431 genes. Eighty point nine percent were carriers for at least one recessive disease. The most common recessive genes showing carrier status were HFE, SERPINA1, GALT, CFTR, BTD, F5, DHCR7, PC, GAA, GJB2, PMM2, PAH, and PKHD1. Twenty-six percent had at least one potential health risk result identified, 20% if the common thrombophilias are excluded. The most common category was hereditary cancer risk (7.5%), followed by F5, F2, and SERPINC1 thrombophilia variants (6.5%), hereditary hemochromatosis 1 (HFE) (4.3%), cardiovascular disorders, mostly cardiomyopathies (3.8%), alpha-1-antitrypsin deficiency or other pulmonary disorder (3.8%), familial Mediterranean fever heterozygotes (1.6%), G6PD deficiency (1.1%), and lipid disorder (0.5%). Two patients had health risks in two areas, and two in three areas. Interestingly, BRCA1 and BRCA2 variants were only identified in males. Thirteen patients, about 7%, had an amended report issued during the period. This happened when an unreported variant of uncertain significance was reclassified as LP or P, or when LP became P, and the performing laboratory issued an amended report. Surprisingly few patients took advantage of the free genetic counseling. No patient adverse events were reported by the participating PCPs despite ongoing outreach, nor by patients. Conclusion: Genomic population health screening can be successfully implemented in primary care settings with use of limited but essential genetic professional assistance, after careful planning and input from other medical specialties. A significant proportion of adults not selected for health status harbors germline genetic variants associated with increased health risk. In the absence of a culture where routine genomic screening is expected and where patient genomic competency is high, PCP capacity limits are a barrier to universality. Inclusion of genes for both health risk results with variable degrees of penetrance and for recessive carrier status, and multiple simultaneous results, dictates careful messaging of the implications, while doing so in a primary care setting begs a concise and efficient process. Rates of carrier detection were in-line with predictions based on general population frequencies. Rates of health risk detections were higher than earlier research programs because a larger number of genes with a much broader scope of health risk was included, including disorders with low penetrance yet meaningful clinical relevance and carefully-designed care pathways meant to optimize care while avoiding unnecessary additional testing. We conclude that genomic population health screening of primary care patients where large numbers of genes are clinically sequenced is feasible in a real-world health system, and that value exists for some tested patients now. Research to overcome certain technical limitations of current clinical genomic testing methods and to better stratify risk level in the context of incomplete penetrance should enhance the value of universally-offered genomic population health screening in the future.

Health disparities stemming from race and ethnicity differences: best practices for reporting demographics in newborn screening research

he recent and persistent COVID-19 pandemic highlights the mounting published data on health disparities in the United States, including higher mortality in minority communities due to systemic racism embedded in our society. Throughout history, “race” has been supposition as a biological variable instead of a social and political construct that has changed throughout history. Using race and ethnicity as variables in human genomic research has had negative consequences for how the research is translated into clinical practice, incorporated into public health programs, and implemented in public policy. Newborn screening (NBS) is one of few public health programs that does not target a particular population and is available to every infant born in the United States regardless of race or socioeconomic status. Each year during the process of screening 4 million newborns for over 80 disorders, state-based public health programs collect a variety of demographic and birth-related data. The potential to leverage the data collected could improve our understanding of diseases and interventions, and in time, could transform healthcare by reducing the health disparity gap. However, inaccuracies or misuse of non-biological variables such as race or ethnicity can lead to social harms and unvalidated conclusions. NBS disorders are screened using a combination of biological and physiological assessments and are conducted either in the birthing hospital or in a state public health laboratory. The laboratory measurements are performed using a blood sample collected on filter paper card. These dried blood spot (DBS) cards also list demographic and birth data that is vital to interpreting test results. Although the list of data collected varies across state programs, most programs collect sex, birth weight, gestational age, the use of antibiotics, feeding type, and/or transfusion status. Residual DBS are a valuable resource and state programs store them for use in program improvement activities and research. Over two-thirds of state programs store residual DBS for longer than one year, and at least 18 include consent for research as one of the collected data points. While NBS research studies often rely on data collected on the DBS card for reliable variables, some of the data represents demographic information provided by the parents and collected at the birthing center. It is not uncommon for healthcare professionals who collect the DBS specimen to infer the newborn’s ascriptive race and/or ethnicity. This leads to potentially inaccurate data that has been used in NBS research studies to characterize study populations and provide conclusions about rare mendelian disorders in specific racial and ethnic populations. The accurate representation of race and ethnicity is always important, especially when a condition is added to nationwide screening. In 2010, NBS for severe combined immunodeficiency (SCID), a life-threating disorder caused by the lack of T-cells, was recommended for nationwide screening. Prior to screening, diagnosed patients that were followed long-term were predominately white (81%). However, a recent publication of screening results from 3.25 million California infants reported that SCID did not occur more frequently in any ethnic group, and found no predominant founder mutation. SCID frequently occurred because of homozygous autosomal recessive inheritance, and 80% of cases have no family history. Accurate representation of race and ethnicity could be used to assess health outcomes and disparities across all racial groups and other biological variables such as genetic ancestry should be considered to help advance the understanding of etiology of SCID.This presentation will exam how race and ethnicity is collected from NBS programs in the United States and how race is used in published NBS literature. Additionally, we will explore the lack of standardized language used to collect information on race and ethnicity in NBS and the incorrect assumption that race and ethnic information is based on parent report. We wil discuss the impact of these practices on NBS research, propose best practices for reporting race and/or ethnicity to ensure accurate evaluation of health outcomes and disparities, and recommend that NBS researchers use other biological variables such as genetic ancestry in research to assess true disease risk

A collaborative genetic carrier screening model for the British Ashkenazi Jewish community.

We present a unique model of a British genetic carrier screening programme for individuals with Ashkenazi Jewish ancestry that exemplifies a partnership between a publicly funded healthcare service (the NHS) and a charity, Jnetics. This model provides affordable access to carrier screening for severe autosomal recessive diseases increased in this community. Prior to the development of this programme, the British healthcare system only provided Tay Sachs' screening for this community, leaving them at higher risk of having a child with a serious autosomal recessive disease. The Jnetics screening programme is promoted through community and social media campaigns, involves educational outreach, a pre-test genetic counselling service by a dedicated NHS-based genetic counsellor, saliva-based DNA testing, comprehensive reporting and, where required, post-test genetic counselling. The charity raises funds to subsidise the screening. In 6 years, the model has been successfully implemented in hospital and community settings and in schools and universities, aiming to reach those pre-conception. In response to the COVID-19 pandemic, the programme adapted by offering genetic screening virtually and has subsequently expanded in its outreach. Furthermore, the screening panel is currently being expanded to include other conditions increased in the Ashkenazi and also the Sephardi and Mizrahi Jewish communities. An example of innovation and accessibility, providing free screening to all students and disadvantaged individuals, the programme aims to provide a model that can potentially be adopted by other genetically at-risk communities.

Global dynamics of COVID-19 epidemic model with recessive infection and isolation.

In this paper, we present an SEIIaHR epidemic model to study the influence of recessive infection and isolation in the spread of COVID-19. We first prove that the infection-free equilibrium is globally asymptotically stable with condition R0<1 and the positive equilibrium is uniformly persistent when the condition R0>1. By using the COVID-19 data in India, we then give numerical simulations to illustrate our results and carry out some sensitivity analysis. We know that asymptomatic infections will affect the spread of the disease when the quarantine rate is within the range of [0.3519, 0.5411]. Furthermore, isolating people with symptoms is important to control and eliminate the disease.

Effect of An 84-bp Deletion of the Receptor-Binding Domain on the ACE2 Binding Affinity of the SARS-CoV-2 Spike Protein: An In Silico Analysis.

SARS-CoV-2 is a recently emerged, novel human coronavirus responsible for the currently ongoing COVID-19 pandemic. Recombination is a well-known evolutionary strategy of coronaviruses, which may frequently result in significant genetic alterations, such as deletions throughout the genome. In this study we identified a co-infection with two genetically different SARS-CoV-2 viruses within a single patient sample via amplicon-based next generation sequencing in Hungary. The recessive strain contained an 84 base pair deletion in the receptor binding domain of the spike protein gene and was found to be gradually displaced by a dominant non-deleterious variant over-time. We have identified the region of the receptor-binding domain (RBD) that is affected by the mutation, created homology models of the RBDΔ84 mutant, and based on the available experimental data and calculations, we propose that the mutation has a deteriorating effect on the binding of RBD to the angiotensin-converting enzyme 2 (ACE2) receptor, which results in the negative selection of this variant. Extending the sequencing capacity toward the discovery of emerging recombinant or deleterious strains may facilitate the early recognition of novel strains with altered phenotypic attributes and understanding of key elements of spike protein evolution. Such studies may greatly contribute to future therapeutic research and general understanding of genomic processes of the virus.