Disease Penetrance Research Articles

MAC Plus Study: A Retrospective Study Correlating DNA Variants, Clinical Course and Outcomes from 187 Patients Who Underwent Testing Using an Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathy Genetic Sequencing Panel

Atypical hemolytic uremic syndrome (aHUS) is a rare, potentially fatal disease that is often difficult to diagnose. The clinical presentation and pathogenesis of aHUS can overlap with several other rare, serious diseases (e.g., inherited thrombotic thrombocytopenia (TTP), shiga-toxin hemolytic uremic syndrome (STEC-HUS), and C3 glomerulopathy (C3G)). In many cases, a positive genetic finding can help clarify the diagnosis, guide treatment decisions, and inform prognosis. We have sequenced >2000 patients with a genetic panel targeting a collection of rare thrombotic microangiopathy (TMA) diseases and here we report the clinical course and outcomes for a subset (n=187). We cataloged all of the rare variants detected from sequencing ADAMTS13, C2, C3, C3AR1, CD46 (MCP), CFB, CFD, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, MASP2, MMACHC, THBD, PLG, WT1 and the variant in C5 causing eculizumab resistance (p.Arg885). We collected data including clinical lab values, potential triggers, diagnoses, treatments, and outcomes. Our cohort here is distinct in that it is not a collection of patients clinically diagnosed with a specific disease (e.g., aHUS); instead, this cohort comprises real-world cases where the physicians sought out genetic testing for their patients as a part of the diagnostic picture. Physicians may be especially likely to seek out genetics when the diagnosis is especially murky. Patients treated with eculizumab responded well (52 responded, 7 did not respond, 8 unknown). Among patients who initiated eculizumab therapy, 34/67 discontinued its use and zero reported disease relapse. Of the 34 discontinuing eculizumab, 8 had a non-aHUS, non-TMA diagnosis while the 33 patients continuing therapy had only 1 with a non-aHUS, non-TMA diagnosis. In this cohort, 38% (71/187) ended up with a diagnosis of aHUS, 14% (27/187) were diagnosed with C3G/C3G-TMA, and 21% (40/187) were diagnosed with some other form of thrombotic microangiopathy (e.g., hypertension-TMA). Only 19 patients had a clear-cut positive genetic finding with 13 of those being the large, homozygous deletion of CFHR1 that is associated with CFH autoantibodies. 52 cases were negative for genetics while 86 had one or more rare variants of unknown significance. The difficulty in interpreting rare variants in the context of very rare, partially penetrant diseases like aHUS underscores the need for more genetic and clinical data to be made publicly available. The collection of data here will be a valuable resource for clinicians and scientists actively conducting research on these rare diseases and perhaps even more valuable for the clinical scientists and genetic counselors seeking context and comparisons for their own patients' variants, where the biggest problem currently is that most rare variants for these diseases are unfortunately variants of unknown significance.

Abstract 12547: Obesity as Risk Factor for Malignant Ventricular Arrhythmias in Phospholamban Cardiomyopathy

Introduction: The pathogenic phospholamban (PLN) p.Arg14del mutation can cause severe arrhythmogenic cardiomyopathy. However, disease penetrance and clinical course are heterogenous and can differ largely between affected individuals. The impact of external factors - such as lifestyle - on the clinical course has not been studied yet. Hypothesis: We hypothesized that obese PLN mutation carriers have worse clinical outcomes, characterized by a higher burden of malignant ventricular arrhythmias (MVA). Methods: PLN p.Arg14del mutation carriers from the Dutch PLN registry with available follow-up (FU) data were included. MVA was defined as either sustained ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter defibrillator intervention or (aborted) cardiac arrest. Patients were categorized into three groups based on their body mass index (BMI): normal weight (BMI 18.5 - 24.9 kg/m 2 ), overweight (25.0 - 29.9 kg/m 2 ) and obese (BMI > 30.0 kg/m 2 ). Mutation carriers with a BMI < 18.5 kg/m 2 or MVA at baseline were excluded. Results: A total of 179 PLN mutation carriers were included in this analysis: 105 (58.7%) normal weight, 59 (33.0%) overweight, 15 (8.4%) obese. The obese group had the highest percentage of MVA (26.7%), followed by the overweight (13.6%) and normal weight (4.8%) groups, as shown in the Kaplan-Meier curve (log-rank 0.016). Continuous BMI was significantly correlated with the incidence of MVA during FU: hazard ratio 1.15 [1.04 - 1.27; p=0.006] per 1-unit increase of BMI, adjusted for age, sex and comorbidities (hypertension, type 2 diabetes mellitus, dyslipidemia, coronary heart disease). Additionally, BMI value predicted MVA with an area under the curve of 0.73 [0.63 - 0.84; p=0.002]. Conclusions: In PLN p.Arg14del mutation carriers, high BMI values and obesity are associated with higher incidence of MVA. This suggests a potential role for lifestyle intervention in the management of this genetic cardiomyopathy.

Abstract 13516: Natural History, Penotypes and Clinical Outcomes in Desmin Related Arrhythmogenic Cardiomyopathy

Background: Mutations in DES gene, encoding the intermediate filament desmin, have been related to arrhythmogenic cardiomyopathy (AC). Our aim is to describe the clinical phenotype, natural history and outcomes in a multicentric international cohort of desmin-related AC patients. Methods: Probands and relatives (85 individuals from 11 families (45% men; mean age 35 [IQR] 23.5-53.5 years old)) carrying a DES mutation from 8 European centers were included. Clinical, electrocardiographical and advanced cardiac imaging data were retrospectively collected and analysed. DES mutations were transfected into cell lines and analyzed by confocal microscopy. Results: Disease penetrance in individuals ≥30 years was 80.8% and 71.4% in individuals <30 years; A left dominant or biventricular form of AC was the main clinical phenotype (69 cases, 81 %). More than half of the patients presented low voltage on the ECG, the mean LVEF was 48.9±16% and the mean RVEF was 53.8±10%. A high prevalence of patients with magnetic resonance imaging (n=30) presented fibrosis (65,2%), with a particular circunferencial (“ring-like”) pattern in 46.4% (Figure A). After a median follow-up of 6 years, 24.7% died (mean age 62[33-76]) (Figure B) and 8.2% suffered appropriate shocks (age 47[31-69.5]) or SD (age 33 [24.5-49]). Finally, there were 6 heart transplants (age 54 [33-68]). A LVEF<50% and male sex were associated with major cardiovascular events. In three DES mutations (E401D, L115E and R415Q) desmin aggreggates were observed (Figure C) Conclusions AC due to DES mutations have a high clinical penetrance as a left dominant or biventricular form of the disease, with an early onset and a high burden of cardiovascular events. A LV “ring-like” LGE pattern was particularly common. Male sex or mildly depressed LVEF were predictors for SD. DES mutation may be pathogenic by causing desmin aggregates. A) Annular pattern of fibrosis B) Carriers free-of-events survival curve. C) Desmin aggregates

Abstract 13141: Age of Onset and Clinical Outcomes in RBM20 -Mediated Arrhythmogenic Dilated Cardiomyopathy

Introduction: Pathogenic loss-of-function variants in the RBM20 -encoded RNA-binding motif 20 splicing regulator cause a severe form of arrhythmogenic dilated cardiomyopathy (DCM). Erroneous splicing of TTN -encoded titin contributes to the pathogenesis of RBM20 -mediated disease. However, studies exploring the clinical course of RBM20 -mediated arrhythmogenic DCM alone or in comparison to TTN -mediated DCM, the most common familial cause of DCM, are lacking. Methods: The Mayo Clinic Genetic Arrhythmogenic Cardiomyopathy Registry (n=391) was used to identify all patients with a pathogenic/likely pathogenic (P/LP) variant in either RBM20 or TTN . For the purposes of this study, a ventricular arrhythmia (VA) event was defined as sudden cardiac arrest, sustained ventricular arrhythmia, or an appropriate ICD shock and an advanced heart failure (AHF) event was defined as ventricular assist device implantation or heart transplantation. Results: Overall, 40 patients with a P/LP variant in RBM20 (50% female) and 70 patients with a P/LP variant in TTN (43% female) were identified. The prevalence of a cardiac phenotype in patients with RBM20- and TTN -mediated disease was 88% and 83%, respectively. RBM20 patients were more likely to have a family history of sudden cardiac arrest (78% vs 34%; p < 0.0001) and cardiomyopathy (90% vs 61%; p=0.001). No difference in rate of ICD implantation (35% versus 33%) was observed. Interestingly, the prevalence of AHF events (10% vs 6%; p=0.5) and VA events (28% vs 24%; p=0.7) was similar between RBM20 - and TTN -positive patients. However, RBM20 patients were younger than TTN patients at the time of their event (37 ± 18 years vs 50 ± 17; p=0.0004). Time-to-event analysis showed RBM20 patients had an earlier time to AHF event (p=0.05) and time to VA event (p=0.03) than TTN patients. The mean age for AHF events was 25 years for RBM20 patients (N=4) and 47 years for TTN patients (N=4). The mean age for VA events was 29 years for RBM20 patients (N=10) and 42 years for TTN patients (N=14). Conclusions: RBM20 -mediated arrhythmogenic DCM represents a highly penetrant genetic heart disease with potentially life-threatening VAs and end stage heart failure manifestations occurring at a significantly younger age in comparison to TTN -mediated DCM.

Do common infections trigger disease-onset or -severity in CTLA-4 insufficiency?

Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

Reduced Penetrance of ALG9-Associated Cystic Kidney Disease in a Real-World Cohort

Reduced Penetrance of ALG9-Associated Cystic Kidney Disease in a Real-World Cohort

Variables associated with progression of moderate-to-severe Crohn’s disease

ObjectiveDetermine the variables associated with hospitalisations in patients with Crohn’s disease and those associated with surgery, intestinal resection, hospital readmission, need for multiple operations and immunobiological agent use.DesignA cross-sectional study...

TRENDS IN PREIMPLANTATION GENETIC TESTING FOR DOUBLE MONOGENIC DISORDERS (PGT-M)

Preimplantation genetic testing for monogenic disorders (PGT-M) can be performed on embryos prior to transfer when a variant or mutation is identified in a single gene. PGT-M has historically been utilized to evaluate embryos for severe, highly penetrant and childhood-onset diseases.1 However, the use of PGT-M has significantly increased due to increased genetic testing3 and expanded indications.4-5

The Contribution of Interleukin (17) in Iraqi Patients with Type I Diabetic and Positive Agglutination Sera with Morganella Morganii Antigens

Background: The rising population of patients with diabetes type 1 has caused in a fast increase in the amount of patients who have diabetic complications. Objective: Isolation of bacteria from diabetic patients and detection of their antibodies in the serum of patients and rabbits. Materials and Methods: Sixty samples of blood and urine were collected from diabetic patients, a similar proportion of genders were included in 50 samples of blood from healthy as controls. Patients with diabetes diseases diagnosed by a physician collected from specialized center for endocrinology and diabetes and Kindy hospital, in Baghdad. Results: This study showed that Morganella morganii (n=9, 18%) was isolated from urine of patients. With M. morganii antigens (complete cells) as three bacteria antigens agglutinated in titer 1:64 and three in titer 1:128 of serum of patients (antibodies) whereas 1 and fife of M. morganii antigens agglutinated in serum of patients in titer 1:256 and 1:16 Consecutively. Determination of the concentration of cytokinetic proteins IL-17, using an ELISA device. The concentration of some inflammation-initiating cytokines was estimated in the serum of the studied samples, which included using IL-17 ELISA technology. The statistical results by t-test showed were significant differences between this interleukin between the patients and the control sample and under the probability level P<0.05 in the serum of the patients compared to the control sample. The results also showed a decrease in the cytokinetic concentration, as the concentration in the infected serum was 0.011 ± 0.019 (pg/mm), while its concentration in the control sample was 0.007 ± 0.033 (pg/mm) in the infected serum. Recognize the agglutination ability slide agglutination exam (anti Morganella morganii rabbit serum). Conclusion: The ability of killed antigen bacteria isolated from diabetic patients to agglutinate with their serum, and its ability to agglutinate with the serum of rabbits injected with this bacterium. The increased prevalence of agglutination and increased antibodies of patients and rabbit blood suggest this as part of the multifactorial basis for disease penetrance and susceptibility.

ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit

APOL1 risk variants are associated with increased risk of kidney disease in patients of African ancestry, but not all individuals with the APOL1 high-risk genotype develop kidney disease. As APOL1 gene expression correlates closely with the degree of kidney cell injury in both cell and animal models, the mechanisms regulating APOL1 expression may be critical determinants of risk allele penetrance. The APOL1 messenger RNA includes Alu elements at the 3' untranslated region that can form a double-stranded RNA structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting on RNA (ADAR)-mediated adenosine-to-inosine (A-to-I) editing, potentially impacting gene expression. We studied the effects of ADAR expression and A-to-I editing on APOL1 levels in podocytes, human kidney tissue, and a transgenic APOL1 mouse model. In interferon-γ (IFN-γ)-stimulated human podocytes, ADAR down-regulates APOL1 by preventing melanoma differentiation-associated protein 5 (MDA5) recognition of dsRNA and the subsequent type I interferon (IFN-I) response. Knockdown experiments showed that recognition of APOL1 messenger RNA itself is an important contributor to the MDA5-driven IFN-I response. Mathematical modeling suggests that the IFN-ADAR-APOL1 network functions as an incoherent feed-forward loop, a biological circuit capable of generating fast, transient responses to stimuli. Glomeruli from human kidney biopsies exhibited widespread editing of APOL1 Alu-dsRNA, while the transgenic mouse model closely replicated the edited sites in humans. APOL1 expression in mice was inversely correlated with Adar1 expression under IFN-γ stimuli, supporting the idea that ADAR regulates APOL1 levels invivo. ADAR-mediated A-to-I editing is an important regulator of APOL1 expression that could impact both penetrance and severity of APOL1-associated kidney disease.

Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population.

Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. We found a prevalence of 1:578, 1:251, and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared with controls, cardiovascular mortality was higher in DCM G+ (odds ratio 1.67 [95% CI 1.04; 2.59], P=0.030), but similar in ARVC and HCM G+ (P≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (odds ratio 3.66 [95% CI 2.24; 5.81], P=4.9×10-7) and HCM G+ (odds ratio 3.03 [95% CI 1.98; 4.56], P=5.8×10-7), but comparable in ARVC G+ (P=0.172). In contrast, ARVC G+ had more ventricular arrhythmias (P=3.3×10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (P=0.009). In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM, or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2-3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression.

Highly malignant disease in early-onset arrhythmogenic cardiomyopathy

Abstract Background Arrhythmogenic cardiomyopathy (AC) is an inheritable and progressive cardiomyopathy characterized by high risk of ventricular tachyarrhythmias and sudden cardiac death. Pediatric patients are underrepresented in AC publications, and the AC penetrance and incidence of cardiac events in children have yet to be determined. Current guidelines recommend initiating family screening in first-degree relatives after age 10–12 years, but the clinical value of this approach has not been systematically evaluated. Purpose We aimed to explore the incidence of severe cardiac events in pediatric patients with AC and to describe the phenotype in early-onset AC. Furthermore, we wanted to estimate the penetrance of AC disease in genotype positive pediatric family members. Methods In a single-center follow-up study, we included consecutive AC pediatric patients and genotype positive family members ≤18 years of age. The patients were followed regularly with electrocardiographic, structural and arrhythmic characteristics according to the AC 2010 Task Force Criteria (TFC). Penetrance of AC disease was defined as fulfilling definite AC diagnosis by the 2010 TFC. We defined severe cardiac events as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias (VAs) (sustained ventricular tachycardia or aborted cardiac arrest). Results We included 62 individuals (11 probands, 51 family members). Fourteen events (5 HTx, 9 VAs) occurred during 6±4 years of follow-up, giving a cumulative incidence of 23% and a yearly incidence rate of 4%. Seven (50%) events occurred in patients ≤12 years of age (Figure 1). All children who underwent heart transplantation were ≤12 years. At inclusion, 13 patients (21%) fulfilled definite AC diagnosis (10 probands, 3 family members). At end of follow-up, AC diagnosis were fulfilled in 20 (32%) patients (11 probands, 9 family members), indicating progression of disease in 7 patients. Mean age at definite AC diagnosis was 13±4 years and 8 patients (40%) were ≤12 years old (Figure 1). All patients diagnosed with AC <12 years of age had biventricular disease with mean LVEF 30±9% and right ventricular fractional area change 21±5% at end of follow-up. Among the family members, 5 (10%) had signs of AC disease at the time of genetic diagnosis. At end of follow-up, AC penetrance was 18% and 3 (6%) experienced severe cardiac events at a mean age of 13±6 years. Conclusion In a pediatric AC cohort of probands and genotype positive family members, we found a high incidence of VA and HTx. Half of the events occurred in children ≤12 years of age, supporting a markedly severe phenotype in early-onset AC. AC penetrance among pediatric family members identified by screening was high, with a significant incident of events. Our findings emphasize the high risk features of early-onset AC disease and indicate a need to start AC family screening in children at an younger age than recommended by current guidelines. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Norwegian Research Council

Sex disaggregated analysis of risk factors for adverse outcomes in hypertrophic cardiomyopathy

Abstract Background Patient sex has been associated with differences in disease penetrance and clinical expression in HCM. We sought to investigate sex-disaggregated differences in risk factors for adverse outcomes in a large international HCM registry. Methods This is a retrospective study of HCM patients from the Sarcomeric Human Cardiomyopathy Registry. Cox proportional hazards models were fit with a sex interaction term to determine significant differences between sexes. Results 6647 (38% women) probands with HCM were included. After a mean follow-up of 6.4 years from first encounter, women had a higher risk of heart failure (HF) composite (HR 1.77; 95% CI 1.56–1.99, p<0.0001), and death (1.22; 1.03–1.45, p=0.02) compared to men. No sex difference existed for ventricular arrhythmia composite (p=0.2) or atrial fibrillation (p=0.6). Sarcomere positive status (Sarc+) and causative variants in MYBPC3 reduced the risk of the HF composite for women, while for men there was no change in risk (P-heterogeneity=0.016 and <0.0001, respectively). Baseline LVEF <35% and larger LA size increased the risk of the HF composite for both sexes but to a greater magnitude in men (P-heterogeneity=0.0003 and 0.04 respectively) (Figure 1). Sarc+ increased the risk of death in men but not women (P-heterogeneity=0.041). Having the HF composite increased the risk of death by 45% in and 240% in men (P-heterogeneity=0.003) (Figure 2). Conclusion There are important sex differences in the risk of heart failure and death in those with HCM, with significant heterogeneity of outcomes based on subgroups defined by genetic and imaging factors. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Sarcomeric Human Cardiomyopathy Registry (SHaRe) is supported by an unrestricted research grant from Bristol Myer Squibb, including funds to individual sites for database support.

Influence of sex on cardiovascular outcomes in RBM20 variant carriers

Abstract Background Variants in the RBM20 gene cause dilated cardiomyopathy and may be associated with a poor prognosis. Objectives To determine disease penetrance, the risk of adverse events and the influence of sex on outcomes in RBM20 variant carriers. Methods Consecutive probands and relatives carrying pathogenic or likely pathogenic RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary endpoint was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF endpoints were also analysed separately and males and females compared. Results Longitudinal follow-up data were available for 163 RBM20 variant carriers (82 male, median age 36.5 years, median follow-up 77.6 months). 10/163 had an MVA event at baseline. 30/153 without baseline MVA (19.6%) reached the primary endpoint with a trend towards worse outcomes in males (p=0.08). 16/153 (10.5%) had new MVA with no difference between males and females (p=0.92). 20/163 (12.2%) developed ESHF (17 males and 3 females; p<0.001). By the end of follow-up, 114 patients (70%) had either left ventricular systolic dysfunction (LVSD) or had experienced MVA. 22 patients received a first diagnosis of LVSD during follow-up. Disease penetrance in individuals over 40 years of age was 78.5% by last evaluation. Eleven patients that reached the MVA endpoint had a left ventricular ejection fraction (LVEF) available within 6 months of the event. Median [IQR] contemporary LVEF was 30% [23.75, 40%]. 5/11 patients had a contemporary LVEF >35%. 1/11 had a contemporary LVEF >45% (a female, 1st degree relative presenting with sustained ventricular tachycardia and an LVEF of 65%). Conclusions RBM20 variants are highly penetrant. The risk of MVA in male and female RBM20 variant carriers is similar but male sex is strongly associated with ESHF. MVA events occur in patients with LVEF >35%. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Clinical Research Training Fellowship

Natural history of MYH7-related dilated cardiomyopathy

Abstract Background Variants in MYH7 are responsible for disease in 1–5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. Objectives We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. Methods We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% females, 35.6±19.2 years) recruited from 29 international centers. Results At initial evaluation, 106 patients (72.1%) had DCM (LVEF 34.5±11.7%). Median follow-up was 4.5 years (interquartile range: 1.7–8.0). 23.7% carriers who were initially phenotype-negative developed DCM. Disease penetrance by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years. Thirty-six percent of patients with DCM met imaging criteria for LV non-compaction. During follow-up, 28% showed left ventricular reverse remodeling (LVRR). Overall incidence of end-stage heart failure (heart transplantation or heart failure related death) was 11.6% at 5 years. Overall major ventricular arrhythmia rate was low (1.0% at 5 years) even among patients with LVEF ≤35% (2.1% at 5 years). LV non-compaction was more prevalent in patients with variants in head domain (S1) (44.2%) compared with other domains (P<0.001). No differences among domain groups were found regarding LVRR, major ventricular arrhythmias or end-stage heart failure. Conclusions MYH7-related DCM is characterized by early age of onset, high penetrance, low rate of LVRR, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, even among patients with severe systolic disfunction. Funding Acknowledgement Type of funding sources: None.

S2733 How to Manage Silent Inflammatory Bowel Disease

Introduction: The incidence and prevalence of inflammatory bowel diseases (IBD), Ulcerative Colitis (UC) and Crohn’s Disease (CD), are increasing worldwide. The pathogenesis of IBD is multifactorial and the disease has a pre-clinical stage where inflammation and damage progress to develop intestinal symptoms. However, some patients in the pre-clinical stage of IBD may be identified on screening modalities. This finding often poses a dilemma as asymptomatic patients may not be willing to initiate medical treatment. Here we describe two cases of pre-clinical IBD found on screening colonoscopy. Case Description/Methods: Patient 1 is an asymptomatic 47-year-old female without significant past medical history who presented for screening colonoscopy. Colonoscopy revealed ileocecal valve stenosis with inflammation that prevented intubation beyond the valve but tissue sample of the ileum was obtained (Figure A-B). Biopsies revealed focal active ileitis with mild glandular distortion and rare pseudopyloric glandular distortion. Magnetic resonance elastography (MRE) showed findings of the terminal ileum with marked bowel wall thickening, luminal narrowing, upstream dilatation suggestive of stricture and penetrating disease with enteroenteric and enterocolonic fistulas. Patient was classified A3/L3/B3. Patient 2 is an asymptomatic 51-year-old female with a past medical history of gastroesophageal reflux disease and anxiety who presented for screening colonoscopy. Colonoscopy was noted to have a patchy, erythematous and ulcerated ileum, and distorted IC valve (Figure C-D). Biopsies revealed severe active ileitis with ulceration. Patient subsequently underwent further workup revealing positive anti-Saccharomyces cerevisiae antibodies (ASCA). Patient was classified as A3/L1/B1. Discussion: Identifying pre-clinical IBD on screening modalities should not dissuade a clinician from appropriately managing moderate to severe cases of IBD. It may be difficult to decide who to treat because such patients are asymptomatic, but persistent inflammation has been shown to be associated with higher rates of hospitalization, surgery, or new abscesses or fistulas. Clinicians can follow up with lower risk patients to monitor symptoms like patient 2, but asymptomatic fistulizing disease and stenoses are high risk like seen in patient 1. Awareness of pre-clinical IBD is important and further discussions about screening and management are warranted.Figure 1.: Screening Colonoscopy of Patients A – Patient 1 Ileocecal valve B – Patient 1 Stenosed Ileocecal valve unable to be traversed C – Patient 2 Normal appearing ileocecal valve D – Patient 2 Terminal ileum ulcer.

SARS-CoV-2 antibody dynamics in blood donors and COVID-19 epidemiology in eight Brazilian state capitals: A serial cross-sectional study.

The COVID-19 situation in Brazil is complex due to large differences in the shape and size of regional epidemics. Understanding these patterns is crucial to understand future outbreaks of SARS-CoV-2 or other respiratory pathogens in the country. We tested 97,950 blood donation samples for IgG antibodies from March 2020 to March 2021 in 8 of Brazil's most populous cities. Residential postal codes were used to obtain representative samples. Weekly age- and sex-specific seroprevalence were estimated by correcting the crude seroprevalence by test sensitivity, specificity, and antibody waning. The inferred attack rate of SARS-CoV-2 in December 2020, before the Gamma variant of concern (VOC) was dominant, ranged from 19.3% (95% credible interval [CrI] 17.5-21.2%) in Curitiba to 75.0% (95% CrI 70.8-80.3%) in Manaus. Seroprevalence was consistently smaller in women and donors older than 55 years. The age-specific infection fatality rate (IFR) differed between cities and consistently increased with age. The infection hospitalisation rate increased significantly during the Gamma-dominated second wave in Manaus, suggesting increased morbidity of the Gamma VOC compared to previous variants circulating in Manaus. The higher disease penetrance associated with the health system's collapse increased the overall IFR by a minimum factor of 2.91 (95% CrI 2.43-3.53). These results highlight the utility of blood donor serosurveillance to track epidemic maturity and demonstrate demographic and spatial heterogeneity in SARS-CoV-2 spread. This work was supported by Itaú Unibanco 'Todos pela Saude' program; FAPESP (grants 18/14389-0, 2019/21585-0); Wellcome Trust and Royal Society Sir Henry Dale Fellowship 204311/Z/16/Z; the Gates Foundation (INV- 034540 and INV-034652); REDS-IV-P (grant HHSN268201100007I); the UK Medical Research Council (MR/S0195/1, MR/V038109/1); CAPES; CNPq (304714/2018-6); Fundação Faculdade de Medicina; Programa Inova Fiocruz-CE/Funcap - Edital 01/2020 Number: FIO-0167-00065.01.00/20 SPU N°06531047/2020; JBS - Fazer o bem faz bem.

Hereditary alpha-tryptasemia: Brief overview of current knowledge and proposal of indications

Human tryptases are serine proteases, which are synthesized nearly exclusively by mast cells (MCs). Immature pro-tryptases, under the form of α- and β-monomers are constantly released by MCs, can be measured in the serum of normal individuals and constitute the basal serum tryptase (bST) level, usually below 6μg/L. By contrast, tetramers of tryptases, which are the mature forms of the enzyme, are normally retained in the secretory granules of MCs. These mature (α- and β-tetramers of tryptase) are only released when MC are activated by different stimuli, leading to a transient increase in serum tryptase level. Such event occurs for instance after IgE-mediated MC degranulation (immediate hypersensitivity reaction). The mature tryptases, through their various biological activities, account for the pathophysiology of immediate hypersensitivity. Of note, recent studies have reported that around 5% of the general population present with increased bST levels related to a genetic trait called hereditary α-tryptasemia (HαT). While there is still a debate on the fact that HαT+ patients may present more frequently various clinical phenotypes, it is now clearly established that the clinical phenotype of patients with primary (clonal) MC disorders, including mastocytosis, is modified by the presence of the HαT trait. In addition, HαT penetrance seems clearly increased in such patients (up to 18% of the cases), leading to the conclusion that HαT is a disease penetrance and phenotype modifier. In the present manuscript, we will describe briefly the genetic patterns of HαT and the clinical phenotypes encountered in HαT+ patients harboring or not a clonal MC disorder. Finally, we will describe the situations when the search for HαT in human can be considered and the preferred method to be used for such investigation.

Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathy.

This study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described. Consecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age. Among 62 individuals [age 9.8 (5.0-14.0) years, 11 probands], 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up. In a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.

SummarySpinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.