Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutionalMLH1epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

The interplay between infection risk factors of SARS-CoV-2 and mortality : a cross-sectional study from a cohort of long-term care nursing home residents

Covid-19 pandemic has particularly affected older people living in Long-term Care settings in terms of infection and mortality. We carried out a cross-sectional analysis within a cohort of Long-term care nursing home residents between March first and June thirty, 2020, who were ≥ 65 years old and on whom at least one PCR test was performed. Socio-demographic, comorbidities, and clinical data were recorded. Facility size and community incidence of SARS-CoV-2 were also considered. The outcomes of interest were infection (PCR positive) and death. A total of 8021 residents were included from 168 facilities. Mean age was 86.4 years (SD = 7.4). Women represented 74.1%. SARS-CoV-2 infection was detected in 27.7% of participants, and the overall case fatality rate was 11.3% (24.9% among those with a positive PCR test). Epidemiological factors related to risk of infection were larger facility size (pooled aOR 1.73; P <.001), higher community incidence (pooled aOR 1.67, P =.04), leading to a higher risk than the clinical factor of low level of functional dependence (aOR 1.22, P =.03). Epidemiological risk factors associated with mortality were male gender (aOR 1.75; P <.001), age (pooled aOR 1.16; P <.001), and higher community incidence (pooled aOR 1.19, P = < 0.001) whereas clinical factors were low level of functional dependence (aOR 2.42, P <.001), Complex Chronic Condition (aOR 1.29, P <.001) and dementia (aOR 1.33, P <0.001). There was evidence of clustering for facility and health area when considering the risk of infection and mortality (P <.001). Our results suggest a complex interplay between structural and individual factors regarding Covid-19 infection and its impact on mortality in nursing-home residents

Accessibility and agglomeration: A theoretical framework for understanding the connection between transportation modes, agglomeration benefits, and types of businesses

While delineating the connection between transportation accessibility and economic activity has long been a topic of interest in geography and regional science, a better understanding of the agglomerative benefits of transportation systems is vital. This paper seeks to tie the concepts of accessibility and agglomeration together by arguing that accessibility benefits ultimately stem from the agglomerative potential created by various transportation investments. This line of reasoning provides an avenue to use the economic mechanisms described in agglomeration theory to analyze the effects of specific transportation modes. To do this, the paper traces the literature on the economic impacts of transportation systems and presents a theoretical framework for understanding the connection between specific transportation modes and specific agglomeration benefits. Ultimately, specific modes have unique features that are more or less conducive to specific agglomeration benefits, to which specific types of businesses also respond. These specific connections are particularly important to understand as the development of new urban transportation modes, for example, autonomous vehicles—and their potential economic impacts—increases rapidly

Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier.

B-cell chronic lymphoproliferative disorders (B-CLPD) encompass a group of hematologic tumors that often present with leukemic involvement.1 Their heterogeneity and the lack of relatively specific diagnostic markers for most of these diseases make their diagnosis challenging, especially in cases that only have blood involvement or when histology is not available. With the currently used immunophenotypic and molecular markers, around 10% of B-CLPD cases remain unclassifiable and are categorized as B-CLPD, not otherwise specified (B-CLPD, NOS). Few recurrent gene mutations and chromosomal abnormalities have been documented in some entities: BRAF and MYD88 mutations in hairy cell leukemia (HCL) and lymphoplasmacytic lymphoma (LPL), respectively,2,3 in addition to the recurrent 7q31–q32 deletion in splenic marginal zone lymphoma (SMZL).1 However, none of them are diagnostic hallmarks of any particular entity. Gene expression profiling studies have recognized specific signatures that identify most common hematological neoplasms.4,5 Based on these results we postulated that the analysis of the gene expression profiling (GEP) of a large series of leukemic B-CLPD could identify specific signatures for each leukemic disease entity. These signatures could be useful for the classification of cases with undetermined diagnosis (B-CLPD, NOS). In this study, we have investigated the GEP of a large series of leukemic lymphoid neoplasms and identified specific gene signatures for most entities that were validated in an independent cohort. We have also derived and validated a simplified quantitative polymerase chain reaction (qPCR)-based 8-gene assay that reliably recognized these entities and could assist in the diagnosis in routine practice, particularly in atypical cases and B-CLPD, NOS

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study