The Correlation of Single Nucleotide Polymorphism of the ACE2 rs4646116 Gene with The Severity of COVID-19

SUMMARY. Different genetic and immunological factors can affect the severity of Coronavirus disease 19. Angiotensin-converting enzyme 2 is a human receptor for Severe Acute Respiratory Syndrome Coro-navirus-2, and the successful interaction between the spike protein of the novel virus and Angiotensin-converting enzyme 2 is responsible for the initial and complete infection. The study aimed to evaluate the correlation between Single Nucleotide Polymorphisms of Angiotensin converting-enzyme 2, with disease severity of Coronavirus disease 19 in AL-Najaf province. The allele Specific-polymerase Chain reaction method was used for investigating Single Nucleotide polymorphisms of Angiotensin converting-enzyme 2 rs4646116 A/G in different states of Coronavirus disease 19 (COVID-19). The wild genotypes (GG) for ACE2 rs4646116 gene recorded a highly significant association p = 0.0009, and a high ratio in the control group (90%) in comparison with moderate cases of COVID-19 (60%). While the heterozygote genotype (GA) of the same gene showed a significant (p-value = 0.0144) and high ratio in moderate cases (30%) in comparison with the control group (10%). Conclusion(s): the wild genotype (GG) for Angiotensin convert-ing-enzyme 2 rs4646116 gene may be associated with more protection from infection with COVID-19. While the polymorphism heterozygote genotype (GA) for the same gene may be associated with more susceptibility to infection with COVID-19.Copyright © 2023, Colegio de Farmaceuticos de la Provincia de Buenos Aires. All rights reserved.

The Effect of Carriage of CYP3A5*3 and CYP3A4*22 Polymorphic Variants on the Safety of Remdesivir Therapy in Patients with COVID-19.

The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods. The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results. Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion. An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.Copyright © Team of Authors, 2022.

An APOL1 genotype associated with adverse Covid- 19 outcomes: UK-Biobank data, September 2021

Introduction/ Background: The risk of hospitalisation/death from Covid-19 in the UK is disproportionately high in black populations. In people of African ancestry, variants of the APOL1 gene (G1 and G2) are associated with risk of noncommunicable diseases, and sleeping sickness. We hypothesise that adverse Covid-19 outcomes are also associated with these variants. Methods: The UK Biobank contains genetic, lifestyle, and health information from 7,643 individuals who self-report as being of black ethnicity. Within this cohort there had been 142 hospitalisations and 36 deaths attributed to Covid-19 as of September 2021. Taking risk factors previously associated with poor Covid-19 outcomes (age, sex, chronic kidney disease, atrial fibrillation, hypertension, depression, chronic obstructive pulmonary disease, dementia, type 2 diabetes, obesity, and Townsend deprivation index) as covariates, we used Firth's Bias Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with hospitalisation and death. Results: Individuals who are heterozygous for variants at both the G1 and the G2 loci are termed G1/G2 compound heterozygotes. G1/G2 compound heterozygosity was associated with hospitalisation (odds ratio = 2.4, 95% confidence interval: 1.2-4.5, p = 0.010) and death (odds ratio = 5.4, 95% confidence interval: 1.8-15.4, p = 0.004). This association has not previously been detected in genome wide association studies, as they usually examine individual loci separately rather than considering combinations of loci. Impact: This has implications at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1 and G2 variants are common, such as West and Central Africa and their diaspora. Conclusion: This data supports hypotheses proposing APOL1 genotype (and specifically G1/G2 compound heterozygosity) as a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry.

EFFECTS OF CESSATION OF VENESECTION IN OLDER PATIENTS WITH HAEMOCHROMATOSIS DURING COVID PANDEMIC

Introduction During the first wave of the COVID- 19 pandemic many elective procedures were postponed including venesection for the treatment of haemochromatosis. On resumption of venesection, limited capacity offered the opportunity to observe the effect of prolonged cessation of maintenance in non-cirrhotic patients over 70 years who guidelines suggest should undergo lifelong venesection. Methods 40 HFE haemochromatosis patients aged 70+ at Royal Derby Hospital (RDH) (25 C282Y homozygotes, 11 compound heterozygotes (CH) and 4 C282Y heterozygotes- 3 mutually exclusive groups) who had a SF< 150mg/L at the point of venesection cessation were identified. SF levels at venesection cessation and resumption were collected and the time interval used to express the change in SF over 12 months. Statistical analyses were conducted using STATA. Results The median projected increase in SF in 1 year in C282Y homozygotes was 40.8(-40.9-490.2)mg/L, in C282Y heterozygotes was 36.4(11.5-157.5) mg/L, and in compound heterozygotes was 74.1(-58.2-170.5) mg/L. There was no significant difference between the projected median increase in SF in 1 year between C282Y homozygotes compared to C282Y heterozygotes (p=0.95, p>0.05), between C282Y homozygotes compared to compound heterozygotes (p=0.72, p>0.05) or between all patients with a single C282Y mutation (compound heterozygotes and C282Y heterozygotes) compared to C282Y homozygotes (p=0.75,p>0.05). Considering all patients requiring venesection, the proportion of patients whose ferritin increased over 12 months by less than 50 was 50%, < 100 was 80% and 98% remain within normal range. Conclusions In non-cirrhotic HFE patients age 70+ the majority of patients can safely suspend venesection for at least 1 year and continued ferritin monitoring would likely reduce the burden on the service without clinically significant consequences as long as a threshold for resumption were agreed. Since evidence suggests that reduced iron absorption may be a physiological result of ageing, some patients may not require further venesection.

HLA-association study with more than 16,000 participants shows no heterozygote advantage for COVID-19 and no protective HLAgenotypes

HLA molecules are key restrictive elements to present intracellular antigens for an effective T-cell response against SARS-CoV-2. HLA alleles vary with respect to their potential to present immunogenic viral epitopes and may therefore determine disease severity. Therefore, we set out to investigate the impact of individual HLA genotypes on the severity of SARS-CoV-2 infections. In August 2020 and July 2021, we performed cross-sectional studies among stem cell donors registered with DKMS in Germany. Volunteers registered for stem cell donation represent a comparable healthy subset of the working age population. Available genetic information was linked to self-reported COVID-19 outcome data. Multivariable regression models were fitted to determine the risk of contracting SARS-CoV-2, severe respiratory tract infection and respiratory hospitalization. More than 200,000 registered donors provided informed consent and participated in the study. Their age ranged from 18 to 61 years. Altogether 16,121 participants donors reported a history of COVID-19. Asymptomatic courses were reported by 1428 participants, mild/moderate symptoms by 10,353 participants, severe respiratory infections by 3913 not requiring hospitalization and respiratory hospitalizations by 427 patients. Notably, we did not observe a heterozygote advantage. The risk for severe infections was not statistically different among individuals with or without homozygosity at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. Of 84 HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles which were prevalent in more than 400 participants only the presence of HLA-B∗39:01 had significant impact on the risk for respiratory hospitalization (OR 2.23, p = 0.01) at a significance level of 1%. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. It is therefore possible that the relatively large viral genome of 29.8 kb encodes for abundant epitopes to mount T-cell responses not limited by the HLA genotype.

Buccal swab testing with the AmplideX PCR/CE SMN1/2 Plus Kit that assesses copy number and critical mutations for SMA

Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease that results from mutation of the survival motor neuron 1 gene (SMN1) and the most common genetic cause of infant death. Approximately 95% of SMA cases are caused by a deletion in both alleles of exon 7 in the SMN1 gene. The copy number of the highly homologous SMN2 gene is an important predictor of the severity of SMA as it has been shown to decrease disease severity in a dose-dependent manner. SMN1 and SMN2 only differ by a few nucleotides, presenting a challenge in determining copy numbers. While carriers typically have one copy of SMN1, cis duplication of SMN1 can produce “silent carrier” (2 + 0) genotypes, which are often associated with two SMN1 variants, c.*3 + 80T>G and c.*211_*212del, that can improve the overall carrier detection rate. SMA treatments SPINRAZA®,, Evrysdi™, and ZOLGENSMA® achieve profound benefits on survival and motor milestones by modifying SMN2 splicing or using gene replacement with functional SMN genes. Early detection of SMA (including SMN2 copy number status) and identification of at-risk couples through carrier screening is critical to aid in early intervention and family planning decisions. We developed an accurate and robust single-tube PCR assay and companion software (AmplideX® PCR/CE SMN1/2 Plus Kit*) that uses capillary electrophoresis (CE) to quantify SMN1 and SMN2 copy numbers (0 to ≥4) and determines the presence/absence of the two SMN1 gene duplication “silent carrier” variants, c.*3 + 80T>G and c. *211_*212del, and the SMN2 disease modifier variant c.859G>C. The SMN1/2 Plus Kit has been previously validated for use with DNA isolated from blood. Here, we verify that DNA isolated from buccal swabs can also be used to determine SMN1 and SMN2 copy number and expanded content using this kit. Materials and Methods: A total of 60 DNA samples isolated from buccal swabs, with varying SMN1/2 copies and other positive and negative variants,were tested using the SMN1/2 Plus kit at a single site (Asuragen). Samples were tested in two cohorts: an initial cohort containing 17 samples isolated from buccal swabs with column or magnetic bead-based methods, and a second cohort of 43 samples isolated from matched blood and buccal samples using column-based methods. PCR products were generated using a Veriti thermal cycler and resolved on Applied Biosystems™ 3500xL, 3130xl, 3730xl, and SeqStudio™ Genetic Analyzers. Raw electrophoresis data (.fsa) files were directly imported into an assay-specific analysis module of the AmplideX® Reporter software that automates peak detection and sizebased classification, SMN1 and SMN2 exon 7 copy number quantification, detection of gene duplication and disease modifier variants, and sample- and batch-level quality control checks. Samples were analyzed using the default (kit calibrator) and user-defined calibration (UDC) (buccal DNA) workflows as described in the protocol. Results: For the initial cohort of 17 Buccal swab samples, SMN1 copy number calls were concordant with MLPA reference results (reported as 0, 1, 2, or ≥3) for 16/17 (94.1%) of samples with default calibration and 17/17 (100%) of samples with UDC. Further, concordance for carrier samples (1 SMN1 copy) were 7/7 (100%) using both methods. SMN2 copy numbercallswere concordant with MLPA reference results for 17/17 (100%) of samples with either default calibration or UDC. For the second cohort of 43 buccal swab samples with matched blood samples, SMN1 and SMN2 copy number calls were concordant with the results from the paired whole blood for at least 95% of samples assessed across the four different CE platforms. All variant status calls were concordant between the buccal swab and whole blood results. Conclusions: Here, we demonstrate that buccal swabs are a compatible DNA source for the quantification of 0, 1, 2, 3, and ≥4 gene copies of both SMN1 and SMN2 and the status determination of three clinically significant variants using the single-tube PCR/CE SMN1/2 Plus kit. Although d fault calibration yielded high rates of agreement between copy number results from buccal swabs and reference results, analyzing samples with user-defined calibration (i.e. calibrating to a buccal swab sample) modestly improved concordance. These results suggest that DNA samples isolated from buccal swabs are compatible with this assay and has implications for more facile sample collection and handling, particularly given the strain of COVID-19 on healthcare infrastructure.

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.

eP455: Fetal ultrasound presentation and neonatal diagnosis of Freeman-Sheldon syndrome in son of previously undiagnosed adult male

Background: Freeman-Sheldon syndrome [distal arthrogryposis type 2A (OMIM #193700), DA2A, Freeman-Burian syndrome] is a rare autosomal dominant multiple pterygium syndrome caused by alterations in MYH3. The phenotypic features, particularly of the face, are distinct and easily recognizable, and the diagnosis can be confirmed with molecular gene analysis. Fetal ultrasound imaging may provide important diagnostic clues to facilitate the diagnostic process. Informed consent and parental permission were provided by the parents. Case presentation: The infant’s mother presented for a Maternal Fetal Medicine genetic counseling telehealth appointment (due to COVID-19 pandemic restrictions) as a G7P2132, 32-year old female who had insulin-dependent diabetes and thrombocytosis. Her partner was a 24-year old male with a history of hearing loss, a V-shaped palate, and a lower lip cleft. Gestational age was 14 4/7 weeks and the indications were: increased nuchal translucency, paternal complex medical history, maternal G6PD heterozygote, and recurrent pregnancy loss. During the genetic counseling session, the following were addressed: 1) Maternal heterozygote status for G6PD indicated that if the fetus was male, there was a 50% chance he would be affected with G6PD-deficiency;2) Increased nuchal translucency on fetal ultrasound (US) with measurement at 98th percentile is associated with an increased risk of chromosomal abnormalities, microdeletion/duplications, and Noonan syndrome. The patient reportedly had low risk cell-free DNA but results were not available to the counselor at the time of consult. The option for additional genetic screening and diagnostic testing was declined;3) Three first trimester pregnancy losses with the father of this baby (FOB) were addressed, and parents deferred chromosome analyses at the time;4) Mother shared FOB’s complex history of bilateral sensorineural hearing loss, V-shaped cleft palate, lower lip cleft, and micrognathia. However, father was not present during the telehealth encounter. Mother was counseled regarding the possibility of an autosomal dominant condition with the potential risk to the pregnancy of up to 50%. It was recommended that the FOB have a clinical genetics evaluation, which could potentially provide a specific diagnosis and inform recurrence risk and management guidance. Follow-up MFM genetic counseling telephone visit occurred with the mother at 31 6/7 weeks gestation due to multiple congenital anomalies evident on fetal ultrasound. A 25 week fetal ultrasound revealed hypotelorism and a thickened nuchal translucency. A repeat study at 29 weeks revealed a V-shaped palate with a possible cleft, micrognathia, and midline mandibular cleft. FOB’s history was revisited. It was determined that he had 3 previous “no shows” to Genetics clinic appointments and did not pursue evaluation after the last counseling appointment. Again, it was emphasized that in order to best make a diagnosis for the family, an affected person would need to undergo a thorough evaluation, including medical and family history review, physical examination, and any indicated genetic testing. The parents were comfortable with the likelihood that the baby had the same condition as the father, but variable expressivity and broad range pf phenotypic presentation were explained. Recommendations for postnatal evaluation of the infant and pertinent genetic testing were provided. Consultative Genetics evaluation of the infant at 2 days of age revealed a short, broad forehead with supraorbital fullness leading to a horizontal brow indentation;mask-like facial appearance;hypotelorism;very deep set eyes with blepharophimosis;deep, creased nasal bridge;small, upturned nose with hypoplastic alae and narrow nares;microstomia with pursed lips;glossoptosis;micrognathia;2 deep vertical chin creases;short neck with excess nuchal skin;inverted and wide spaced nipples;clenched hands with 5th digits overlying 4th and 2nd overlying 3rd, bilaterally;bilateral vertical talus;2nd toes longer and overlying rd toes;clinodactyly of 4th and 5th toes bilaterally;and deep gluteal crease with no visible sinus. There were no evident contractures. The father has a complex history with no medical assessments prior to age 18. He reported that he did “not look like anyone else” in his family. He has a diagnosis of autistic spectrum disorder, a submucous cleft, vision issues, hearing loss necessitating a hearing aid on the left, and a history of cholesteatomas and of mastoidectomy. On brief examination, he had a mask-like face, blepharophimosis, left microphthalmia, left esotropia, narrowing of his midface, deep vertical crease on the mandibular region, microstomia, broad great toes, single flexor creases on the thumbs, and contracture of right thumb. Maxillofacial CT of the infant revealed hypoplastic mandibular body, ramus, and condyles bilaterally with micrognathia and retrognathia;hypoplastic maxilla bilaterally;and enophthalmos with retracted appearance of globes in the bony orbits bilaterally. Multiple facial bone abnormalities were seen, including microsomia, micrognathia, retrognathia, orbital hypotelorism and enophthalmos Genetic testing was performed via a custom Whole Exome Slice at GeneDx laboratories and included the MYH3 and TNNI2 genes. Results revealed a heterozygous pathogenic change in MYH3 (c.2015 G>A;p. R6724) consistent with the diagnosis of Freeman-Sheldon syndrome. Conclusion: The presentation of “midline mandibular cleft” on fetal ultrasound was the most specific prenatal finding. This is a very rare fetal finding. Thus, it should prompt further evaluation to assess for true clefting versus ridging or creasing. Additionally, targeted assessment for other findings or clinical clues for Freeman-Sheldon syndrome, such as contractures, “windmill vane” hand, and mouth size, could aid in the differential diagnosis considerations and the diagnostic process. Admittedly, these are position and quality dependent, and are challenging to assess even in ideal situations. The phenotype of the father was immediately recognizable. However, due to COVID-19 pandemic restrictions, prior to the infant’s birth, only telehealth visits were conducted and the father’s participation was by telephone. This limited the ability to narrow the differential diagnosis without visualization of his distinct phenotypic features. Finally, missed opportunities to diagnose the father prior to this pregnancy occurred. Many clinics send “no show” letters to referring providers and patients, as we do. Emphasizing the importance of diagnosis prior to pregnancy for individuals concerned about having a genetic disorder should be considered as part of the information shared in these letters.

Prenatal genetic screening and diagnostic testing during the COVID-19 pandemic in the Bronx, NY

Introduction: The Coronavirus Disease (COVID-19) pandemic has changed the landscape of both inpatient and outpatient healthcare. During the height of the pandemic, most elective and many nonelective procedures were halted. Prenatal care services including ultrasound and genetic screening and testing remained active (given gestational age dependence) while shifting from in-person towards telehealth counseling. NewYork Citywas at the epicenter of the pandemic fromMarch through June 2020. Elective procedures at Montefiore Medical Center, which serves a diverse urban population in the Bronx, NY,were cancelled from March 16, 2020 to June 20, 2020. Prenatal ultrasound shifted from a dating ultrasound and a nuchal translucency ultrasound to one first trimester ultrasound and anatomy scans were scheduled at 20–22 weeks gestation rather than 18–20 weeks. The majority of counseling sessions were conducted via telehealth and prenatal diagnostic procedures (including amniocentesis and chorionic villus sampling [CVS]) were performed with a limited team to adhere to COVID-19 protocols. We examined the impact of this shift on rates of prenatal genetic screening and diagnostic procedures before and during the COVID-19 pandemic. Previous literature has revealed that since the advent of noninvasive prenatal screening (NIPS), prenatal genetic diagnostic procedures rates have been on the decline.We hypothesized that the rate of genetic diagnostic procedure rates would decrease and NIPS would increase as compared to the similar period in 2019. Methods: Retrospective analysis of data collected in a secure institutional logbook at Montefiore Medical Center Department of Obstetrics & Gynecology and Women’s Health (Division of Reproductive and Medical Genetics and Division of Fetal Medicine and Ultrasound) from January 1, 2019–December 31, 2020. Collected data included number of procedures, gestational age, and indication for procedure (categorized as advanced maternal age (AMA), ultrasound anomalies, positive screening test, hereditary disease in the family possibly affecting fetus (including family history or genetic carrier), or other. Procedures for multiple gestations were considered as a single procedure.. Results: 503 diagnostic procedures (359 amniocenteses and 144 CVS) were included. Most common indication (ultrasound anomaly) and average gestational age (13 weeks for CVS and 19 weeks for amniocentesis) were the same in 2019 and 2020. In total, 275 procedures were performed in 2019 as compared to 228 in 2020 (20.6% decrease) ( p = 0.018). Specifically, amniocentesis decreased from 187 to 172 (8% decrease) ( p = 0.214) and CVS decreased from 88 to 56 (36% decrease) ( p = 0.004). NIPS increased from 1,312 tests in 2019 to 1727 tests in 2020 (31.6%) ( p < 0.001). The same data points were then analyzed during the four-month period at the height of the pandemic in New York City. We compared numbers of procedures from the period March 1, 2019–June 30, 2019 to March 1, 2020–June 30, 2020. Total prenatal diagnostic procedures during this period were 91 in 2019 and 81 in 2020 (12.3% decrease). This included 59 amniocenteses compared with 60 in the same period in 2020 (1.6% increase) and 32 CVS in 2019 compared to 21 in 2020 (34.3% decrease). Noninvasive prenatal screening increased from 348 to 510 (increase of 46.5%) during this period. Discussion: At Montefiore Medical Center in the Bronx, NY, prenatal genetic diagnostic procedures decreased while NIPS rates increased during the pandemic. This trend may reflect patient’s concerns for a COVID-19 exposure during in-office procedures, shift to telehealth counseling, or be reflective of the overall trends seen since the widespread offering of NIPS to prenatal patients. The decrease in CVS may be explained by an intentional system delay of combining ultrasound and blood draw to a single visit at the end of the first trimester. Future studies should investigate how access to care and gestational age at the time of presentation influenced prenatal genetic screening and testing cho ces during the pandemic, in order to better explain the identified trends.

A rare disease in the community hospital: Hemophagocytic lymphohistiocytosis (HLH) needs immediate local attention for early recognition and individualized treatment

Purpose: HLH is a severe hyperinflammatory syndrome characterized by highly active cytotoxic T-cells, NK-cells, and macrophages. If undiagnosed, HLH can lead to multiorgan damage and death. Conditions triggering HLH are infections, malignancies and autoimmune/-inflammatory (MAS-HLH) disorders. Immunosuppressive patients are prone to develop infection triggered HLH. The incidence in the European community hospital is unknown, as is the number of unrecorded cases. HLH-patients, diagnosed at a single communal hospital with an adjacent catchment area of 500,000 citizens, were reviewed in the context of national and international guidelines. Methods: From 08/2016 to 11/2020, 13 HLH patients were analysed retrospectively. Both HLH-2004 criteria and the web-based Hscore were used to diagnose HLH. The collected data depicts clinical presentation, underlying disease, laboratory findings, and treatment. Results: This Study includes 13 HLH-patients (10 male). Median age at diagnosis was 53, ranging from 27-80 years. Most common triggers in our cohort were infections (n=7) and malignancies(n=4). MAS-HLH (n=1) was seen in a Still's disease patient. HLH-related gene mutation was identified (n=1) with a heterozygote mutation in Perforin (PrfA91). Lymphomas of B-as well as T-cell origin (n=2) and AML (n=3) represented main cause in malignancy associated HLH. Viral infections i.e., COVID-19(n=1), RSV (n=1) and EBV (n=1), also bacterial infections like M. tuberculosis (n=1), and the attenuated strain BCG (n=2) were seen in infection associated HLH. Most patients presented with fever (n=9) and splenomegaly (n=4). HLH patients show pancytopenia, peak ferritin levels ranging 1352-185000 ng/ml (median=21600), peak soluble IL-2 receptor levels ranging 2571-21660 U/ml (median=6606), and peak triglyceride levels ranging 175-610 mg/ml (median=227). Hemophagocytosis in bone marrow was found in 6 patients. First line therapy was glucocorticoids (n=12) combined with polyvalent immunoglobulins. Etoposide (n=5) and chemotherapy (n=4) were given to malignancy triggered HLH. Rituximab was applied in EBV-triggered HLH. Anakinra (n=3) and Ruxolitinib (n=4) was given to selected patients. Two patients received cytokine-depletion using adsorption columns Cytosorb®. Multiorgan failure (n=5) was the most common cause of death. Conclusion: This data provides incidence estimation of HLH in adult patients. Institutional and national measures will be presented to prevent death due to HLH.

P.0177 Partial ornithine-transcarbamylase deficiency, autoimmunity and psychosis – a complex case report

Background: Ornithine-transcarbamylase deficiency (OTC) is the most common type of urea cycle disorder, and it is the only one with X-linked inheritance. The clinical presentations can vary from severe symptoms caused by hyperammonemia in childhood or adolescence to milder cases with late-onset in adulthood (similar to delirium or acute psychosis) [1], in the context of precipitating factors such as pregnancy, high protein intake, acute stress, infections, certain medications (valproate, steroids, haloperidol) [2]. Method: We present a case of a 31-year-old female, with no history of mental disorders, with a personal history of Hashimoto thyroiditis and urticaria, and a family history of OTC deficiency (her two-year-old niece). She was also a heterozygous carrier for the OTC deletion, reporting periods of meat avoidance and anorexia. She was single, lived alone, and complained of work-related stress, mainly as she worked from home during the COVID-19 pandemic as an IT consultant. The patient presented at our clinic in emergency for psychomotor agitation, slurred speech, complex auditory and visual hallucinations, and mystical delusional ideas. Furthermore, one week before her presentation, she started fasting because of her Christian orthodox religious beliefs (before Easter celebration), but she also complained of insomnia, fatigue, and tachycardia. The patient reported being vaccinated with the first dose of Pfizer's SARS-CoV-2 vaccine one week before the presentation. Results: Laboratory tests showed iron-deficient anemia and ketonuria;hepatic function was normal. Thyroid function was also normal, but anti thyroperoxidase antibodies were elevated. Serum ammonia levels were normal, and urinary orotic acid levels were within normal range. The result of head CT was unremarkable. Neurological examination was normal. She was started on 10 mg i.m. Haloperidol per day, but given the possibility of inducing hyperammonemia in urea cycle disorders patients, she was switched to Risperidone 6 mg/day, which was gradually reduced to 3 mg/day. Also, she was started on a protein-restricted diet. On the second and third days of admission, she was partially disoriented and somnolent but showed no signs of metabolic encephalopathy;therefore, metabolic treatment was not initiated. On the sixth day, she was almost completely recovered, with no psychotic symptoms. After the remission of psychotic symptoms, the neuropsychological evaluation showed significant cognitive deficits: executive functions (impaired performance on Tower of London task), deficits of focused and distributed attention, and decreased immediate verbal memory, even though the patient had received higher education, being at the top of her class during her studies. Given that metabolic profiles were normal, we discuss the complex interactions between autoimmune disorders, genetic factors, precipitating factors, and psychosocial factors that could have contributed to the psychotic episode. Conclusion: Clinicians should consider various factors that can influence the psychological state of a patient, paying attention to atypical factors or symptoms. Also, regarding the treatment of psychiatric symptoms in patients with urea cycle disorders with a normal metabolic profile, psychiatrists must avoid certain medications (haloperidol, valproate) that can worsen the patient's status. No conflict of interest