Lymphoproliferation- a clue towards an underlying monogenic disorder of immune dysregulation- a retrospective analysis from a single center in India

Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.

THE UNEXPLORED POSSIBILITIES, PERCEPTIONS AND ETHICAL IMPLICATIONS OF GENE-EDITING ALLERGIC DISEASE: ENGAGING STAKEHOLDERS IN SOUTH AFRICA

Clinically approved cell and gene therapies are opening up future possibilities to treat and prevent myriad diseases, which may include allergic diseases. In South Africa, this could help alleviate the high disease burden and economic cost of treating such diseases. However, even if viable gene-editing options to treat, cure and prevent allergic diseases become safe, effective and affordable for the South African market within the next few decades, the ethical implications and challenges of perceptions, regulation and oversight to ensure safety and equitable access remain. It would be important for all stakeholders involved, including the public and physicians, clinicians and ethicists on clinical and research ethics committees, to be informed about the possibilities, to engage in discussions with one another and to redress any gaps in knowledge. It would be especially important to determine whether cases for gene-editing aimed at allergy would be applied for therapeutic purposes or for enhancement. Much research and discussion remain to be embarked upon;however, it is imperative that research and engagement are expanded and prioritised.

Abstracts from the 54th European Society of Human Genetics (ESHG) Conference

The proceedings contain 1623 papers. The topics discussed include: the COVID-19 host genetics initiative - an international, open science effort to identify genetic risk factors for COVID19 severity and susceptibility;clinical implementation of RNA sequencing for Mendelian disease diagnostics;local gene co-expression measurements in single-cells highlight inter-individual specificity;a cross-disorder dosage sensitivity map of the human genome;biallelic ATG7 variants impair autophagy leading to neurological disease;epilepsy polygenic risk scores in >269k individuals with and without epilepsy;machine learning methods for prioritizing genetic variants;Mendel Lecture - Cell-free DNA in plasma: coming in different sizes and shapes;imaging the accessible genome at nanometer scale;retrotransposition in brain: does LINE activity in the central nervous system matter?;activation of transposons in neurological disorders;how to transfer genomic data internationally in compliance with the GDPR;mutational signatures of environmental agents and chemotherapeutics in human cellular models;and the art, science and practice of implementing genomics in clinical care.

POSB222 Can Gene Therapy Prices Remain the Same? What We Have Learned from the COVID-19 Vaccines

Objectives: Gene therapies (GTs) have been progressively reaching the market in the past years, despite the often high per-patient costs associated. This high cost has in part been justified by the small target patient population and the high research and development cost associated with GTs. However, in the light of newly approved, low-cost gene therapies, with a vast addressable market, such as the Moderna Covid-19 mRNA vaccine, the question becomes, what impact will this have on the future of GT pricing. The objective of this study was to analyse the pricing of marketed gene therapies, and if there is a link between their price and their addressable market. Methods: We identified all EMA approved GTs in the United Kingdom up to the year 2021. We analysed the addressable market for each treatment, and where possible, found their list prices as cited by the NHS and/or NICE. Then we analysed the correlation between the prices and the addressable market. Results: We found a clear tendency for the prices of gene therapies to rise when the addressable market became smaller. We hypothesise whether new GTs arriving to the market can be priced according to the same price-volume correlation line, as it has been shown that the innovation can be provided at a small cost. Considering monogenic diseases, one could regard that providing and delivering genetic material is a ´me-too´ intervention now that mRNA vaccines have been effectively rolled out on a large scale and at an affordable cost. Conclusion: Novel mRNA vaccines have set a new standard for the pricing of GTs, and it could be that the willingness to pay for the replication of that innovation is low, thus killing the ‘hen of the golden eggs’.

Utilization of in-patient genetic testing services at Duke University Health System

Background: Reduced costs and rapid turn-around times for next generation sequencing testing has resulted in an increase in genetic test utilization for hospital patients. Over the past several years, Duke University Health System has implemented vendor standardization and third party billing agreements with external reference laboratories for outpatients. While these efforts have resulted in a cost savings of approximately 9.6 million dollars annually, send-out expenses for genetic testing of hospital patients remains high. Currently, exome sequencing is the only genetic test that requires pre-approval by laboratory leadership prior to send-out on hospital patients. Purpose: To review the utility of inpatient genetic testing to determine if institutional guidelines and a review process are needed to ensure appropriate utilization. Method: In-patient genetic test orders were retrospectively reviewed to determine the clinical utility of tests ordered during hospital encounters from July 1, 2019 to June 30, 2020. Results: In total, 269 molecular tests were ordered during a hospital encounter in FY2020. The majority of these tests (223) were ordered in blood for germline testing with a minority (46) of tests ordered in tumor for somatic testing. In patients with a clinical suspicion of a Mendelian disorder, gene panels were ordered with the highest frequency (77%). Of the gene panels sent for testing, epilepsy-related gene panels were ordered most frequently with ∼50% of these requested with STAT turnaround. Exome sequencing was approved for send-out 15 times in FY2020 with 6 of these requested with STAT turnaround. Of the 6 STAT exomes, 3 resulted in a diagnosis for the patient, two were negative, and one was uncertain. In total, 70% of test results were received after patient discharge and the diagnostic yield was 15%. Of the results with a positive diagnosis, only 4% were received prior to discharge. Interestingly, 31% of orders were placed within 48 hours of patient discharge and multiple genetic tests were ordered on a single encounter in 7 patients. While the total send-out expense of germline genetic testing was calculated at ∼$585,000, we estimate that the quantity and expense of genetic tests in FY2020 may be lower than normal due to COVID-19 impact. Review of orders for somatic testing identified one physician where 96% of orders did not meet the 14-day rule, a Centers for Medicare and Medicaid Services laboratory date of service policy exception that allows molecular or genetic tests to be ordered on a surgical specimen and billed directly by the performing laboratory when the test is ordered 14 or more days post patient discharge. The physician has since been notified and informed of the 14-day rule and the requirements for send-out testing of molecular tests. Conclusion: Retrospective review of inpatient genetic testing revealed that gene panels, which do not currently require prior approval, are ordered with the highest frequency. Further review revealed that a majority of test results were received after patient discharge and subsequently not utilized for direct patient care during that encounter. As a result, laboratory leadership is working to implement test utilization strategies to improve patient care by developing metrics of appropriate and inappropriate utilization, as well as developing a systematic framework and infrastructure to track the use and clinical utility of genetic testing for inpatients.

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