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Abstract Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4–69.3; P = 1.3 × 10−7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

PURPOSEDiagnosis of AIDS lymphoma in low-resource settings, like South Africa, is often delayed, leaving patients with limited treatment options. In tuberculosis (TB) endemic regions, overlapping signs and symptoms often lead to diagnostic delays. Assessment of plasma cell-free DNA (cfDNA) by next-generation sequencing (NGS) may expedite the diagnosis of lymphoma but requires high-quality cfDNA.METHODSPeople living with HIV with newly diagnosed aggressive B-cell lymphoma and those with newly diagnosed TB seeking care at Chris Hani Baragwanath Academic Hospital and its surrounding clinics, in Soweto, South Africa, were enrolled in this study. Each participant provided a whole blood specimen collected in cell-stabilizing tubes. Quantity and quality of plasma cfDNA were assessed. NGS of the immunoglobulin heavy chain was performed.RESULTSNine HIV+ patients with untreated lymphoma and eight HIV+ patients with TB, but without lymphoma, were enrolled. All cfDNA quantity and quality metrics were similar between the two groups, except that cfDNA accounted for a larger fraction of recovered plasma DNA in patients with lymphoma. The concentration of cfDNA in plasma also trended higher in patients with lymphoma. NGS of immunoglobulin heavy chain showed robust amplification of DNA, with large amplicons (> 250 bp) being more readily detected in patients with lymphoma. Clonal sequences were detected in five of nine patients with lymphoma, and none of the patients with TB.CONCLUSIONThis proof-of-principle study demonstrates that whole blood collected for cfDNA in a low-resource setting is suitable for sophisticated sequencing analyses, including clonal immunoglobulin NGS. The detection of clonal sequences in more than half of patients with lymphoma shows promise as a diagnostic marker that may be explored in future studies.

AbstractObjectivesWe sought to determine hemodynamic effects of aortic paravalvular leak (PVL) and predictors of clinical outcomes after aortic PVL closure.BackgroundThe significance of hemodynamic alterations in PVL and relation to severity, procedural success of percutaneous closure and clinical outcomes have not been defined.MethodsPatients undergoing percutaneous PVL closure between July 21, 2004 and September 10, 2018 were included. PVL severity was assessed by echocardiography and aortic angiography. Hemodynamics were assessed by intra‐arterial pressure tracings before and after PVL closure. The primary outcome was a composite of mortality, redo aortic valve replacement (AVR) and redo PVL closure.ResultsOne hundred and seventeen patients (mean age 70.3 ± 14.9 years, 79% surgical and 21% transcatheter prostheses) underwent PVL closure with 94% technical success. PVL was moderate or greater in 106 (91%) at baseline and 11 (11%) post‐procedure. Diastolic BP for those with moderate or greater PVL was lower than for those with less PVL (50.3 ± 11.7 vs. 56.5 ± 12.4 mmHg, p < .001). Pulse pressure was similar between these groups (69.9 ± 20.3 vs. 67.4 ± 21.2 mmHg, p = .39). 35 patients (34%) had 40 events during a mean follow‐up of 1.6 ± 1.9 years (23 deaths, 12 redo AVR, and five redo PVL closures). In a multivariate model, final diastolic BP <47 mmHg (HR 3.27 [1.45–7.36], p = .007) was a significant predictor of the composite endpoint.ConclusionsDiastolic BP was significantly associated with aortic PVL severity and clinical outcomes after PVL closure. In contrast, pulse pressure did not correlate with PVL severity or outcomes. These findings have implications for clinical management of patients with aortic PVL.

Background. Anesthetic management of orthotopic liver transplantation (OLT) can be challenging. Management involves responding to sudden hemodynamic shifts, addressing instability, and performing ongoing volume assessment. To best prepare for these perturbations, various monitors are used intraoperatively. We sought to explore the impact of transesophageal echocardiography (TEE) and pulmonary artery catheter (PAC) use on outcomes of patients undergoing OLT. Methods. We retrospectively reviewed records of patients who underwent OLT at a single institution and included all who were monitored intraoperatively with TEE alone, PAC alone, or both methods concurrently (TEE + PAC). We determined whether these groups had differences in length of hospitalization (primary outcome), 30-day mortality rate, and other outcomes. Results. Three hundred eighteen liver transplant operations were included in the study. Patients in the TEE + PAC group had the shortest median length of hospitalization (TEE + PAC, 8.6 days; TEE, 10.3; PAC, 9.1; P = 0.04). The TEE + PAC group also had the lowest 30-day mortality rate (TEE + PAC, n = 1 [1.3%]; TEE, n = 5 [12.8%]; PAC, n = 7 [3.5%]; P = 0.009). However, the TEE + PAC group also had the highest rate of a new postoperative need for dialysis (TEE + PAC, n = 8 [10.3%]; TEE, n = 2 [5.1%]; PAC, n = 1 [0.5%]; P < 0.001). Conclusions. Compared with either TEE alone or PAC alone, intraoperative monitoring with TEE + PAC during OLT was associated with the shortest length of hospitalization and lowest 30-day mortality rate. Transplant anesthesiologists should be aware of the potential benefit on patient mortality and hospital length of stay with concurrent intraoperative TEE + PAC monitoring and the increased need for new postoperative dialysis.

Background. The assessment of perioperative risk factors for the development of acute respiratory distress syndrome (ARDS) has been described in various surgical populations. However, there are only limited data among patients undergoing liver transplantation (LT), particularly regarding the influence of intraoperative ventilation parameters. We sought to identify the perioperative risk factors associated with the development of ARDS in LT recipients. Methods. This is a single-center, retrospective cohort study of adult patients who underwent LT at a tertiary academic medical center between January 1, 2006, and January 31, 2016. Postoperative ARDS was identified using the Berlin definition. Multivariable logistic regression analysis was used to identify perioperative risk factors for ARDS. Results. Of 817 eligible patients who underwent an LT during the study period, 20 (2.45%) developed postoperative ARDS. In the preoperative model, ongoing dialysis (odds ratio, 6.41; P < 0.01) was identified as an independent risk factor of ARDS post-LT. A higher mean peak inspiratory pressure per increase of 1 cm H2O (odds ratio, 1.31; P < 0.01) was the only independent risk factor in the intraoperative model. Patients who developed ARDS postoperatively had significantly greater intensive care unit and hospital stay compared to non-ARDS patients (P < 0.001). There were no significant differences in the 30-day (P = 0.16) and 1-year (P = 0.51) mortality between the groups. Conclusions. Dialysis at the time of transplant and elevated intraoperative mean peak inspiratory pressure were associated with the development of ARDS. ARDS post LT was associated with increased intensive care unit and hospital length of stay, but not increased mortality.

Introduction. Acquired severe aplastic anemia (SAA) is a life-threatening disorder characterized by severe progressive pancytopenia and hypocellular bone marrow. The etiology of acquired SAA is not understood but believed to be related to abnormal immune responses to environmental exposures. We conducted a genome-wide association study (GWAS) to identify common germline variants associated with SAA. Methods. We identified 895 patients with SAA who underwent related or unrelated hematopoietic cell transplant (HCT) with clinical data and pre-HCT blood samples available in the Center for International Blood and Marrow Transplant Research (CIBMTR) database and biorepository. Pre-HCT DNA was extracted from blood of patients with SAA and genome-wide genotyping was conducted using the Illumina OmniExpress array. We excluded 93 inherited bone marrow failure cases. The SAA cases were grouped cases into discovery and validation sets based on time of batch sample receipt. Analyses were limited to patients of European ancestry based on principal component analyses to minimize the potential effect of population stratification. Controls were genomically matched and selected from previously scanned cancer-free subjects at the Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, NCI. The final analysis included 534 acquired SAA cases (359 in the discovery set and 175 in the validation set), and 2,455 controls (1,396 in the discovery set, and 1,059 in the validation set). Results. Patients with SAA in this study received HCT between 1989-2015 at a median age of 21 years, 56% were male, and the median time between SAA diagnosis and HCT was 11 months. Strong genome-wide association signals were identified across the human leukocyte antigen (HLA) genes encoded at the major histocompatibility complex (MHC) on chromosome 6p21 (Figure 1). The top SNP was located in the P4 binding pocket of the HLA class II gene HLA-DPB1(rs1042151A>G, p.Met105Val, pooled-odds ratio [OR]=1.75, 95% confidence interval [CI]=1.50-2.03, p=1.94x10-13). The expression of HLA-DP in CD19+ cells from 175 healthy donors was significantly different by rs1042151 A>G genotype (p=2.04x10-6) (Figure 2). A second SNP near HLA-B, rs28367832G>A, also reached genome-wide significance (pooled-OR=1.49, 95% CI=1.22-1.78, p=7.27x10-9). Copy-number variant analysis and next generation sequencing also identified somatic, clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes in 8.6% of the SAA cases and none of the controls. Conclusion. This SAA GWAS identified strong association signals between common germline genetic variants in HLA class I and II genes and SAA. The main SNP is associated with changes in HLA-DP expression suggesting a key role for this locus in SAA etiology. This study adds further evidence to the connection between SAA and immune dysregulation. Disclosures Cerhan: Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Celgene: Research Funding. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.