Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Sirolimus Early Treatment in Vascular Anomalies Leads to a Better Response

Objectives:. Sirolimus has become a relevant drug in the treatment of vascular anomalies, initially relegated to rescue therapy for refractory lesions but more recently has become first line. Our objective is to determine when it is best to start sirolimus treatment. Methods:. A retrospective review of patients with vascular anomalies treated with sirolimus during a 9-year period was performed. The variables analyzed included subtype of vascular anomaly, age at the start of treatment, sirolimus dosage and levels, response, and duration of treatment among others. Results:. One hundred twenty-two patients were included and classified according to ISSVA in: tumor (7), lymphatic malformation (60), venous malformation (16), combined malformations (18), associated overgrowth (8), and others (15). Overall response was positive in 90.8%. Median duration of treatment was 32 months (0–116). Response was not influenced by dosage or levels, neither by the subtype of vascular anomaly, location, extension, symptoms, genetic testing nor previous treatments. However, the lower the age of starting sirolimus, the better the response, mainly under 5 years of age (P = 0.004). At 6 months, 67% of patients had responded while at 12 months >84% did. By age, patients 5 months from older patients. Time until a positive response was not influenced by subtype or severity. Conclusion:. Overall response to sirolimus was good and most patients responded irrespective of their severity in location, extension or symptoms. Patients <5 years old respond better and faster making our goal to attempt for an early treatment

A six-attribute classification of genetic mosaicism

Mosaicism denotes an individual who has at least two populations of cells with distinct genotypes that are derived from a single fertilized egg. Genetic variation among the cell lines can involve whole chromosomes, structural or copy-number variants, small or single-nucleotide variants, or epigenetic variants. The mutational events that underlie mosaic variants occur during mitotic cell divisions after fertilization and zygote formation. The initiating mutational event can occur in any types of cell at any time in development, leading to enormous variation in the distribution and phenotypic effect of mosaicism. A number of classification proposals have been put forward to classify genetic mosaicism into categories based on the location, pattern, and mechanisms of the disease. We here propose a new classification of genetic mosaicism that considers the affected tissue, the pattern and distribution of the mosaicism, the pathogenicity of the variant, the direction of the change (benign to pathogenic vs. pathogenic to benign), and the postzygotic mutational mechanism. The accurate and comprehensive categorization and subtyping of mosaicisms is important and has potential clinical utility to define the natural history of these disorders, tailor follow-up frequency and interventions, estimate recurrence risks, and guide therapeutic decisions.Peer reviewe

Array CGH Analysis of Paired Blood and Tumor Samples from Patients with Sporadic Wilms Tumor

Submitted by sandra infurna ([email protected]) on 2016-03-01T16:49:50Z No. of bitstreams: 1 fernando2_vargas_etal_IOC_2015.pdf: 477665 bytes, checksum: 7b0ca95990e0ab5295b7e7bec530658b (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-03-01T17:11:58Z (GMT) No. of bitstreams: 1 fernando2_vargas_etal_IOC_2015.pdf: 477665 bytes, checksum: 7b0ca95990e0ab5295b7e7bec530658b (MD5)Made available in DSpace on 2016-03-01T17:11:58Z (GMT). No. of bitstreams: 1 fernando2_vargas_etal_IOC_2015.pdf: 477665 bytes, checksum: 7b0ca95990e0ab5295b7e7bec530658b (MD5) Previous issue date: 2015Instituto Nacional de Câncer. Divisão de Genética. Rio de Janeiro, RJ, Brasil.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain / CIBERER. Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain / CIBERER. Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain.Instituto Nacional de Câncer. Divisão de Patologia. Rio de Janeiro, RJ, Brasil.GT-CSGP Working Group.Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Hospital Universitario La Paz. Section of Clinical Genetics, . Madrid, Spain.CIBERER. Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain / Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Hospital Universitario La Paz. Section of Clinical Genetics, . Madrid, Spain.Universidade Federal do Rio de Janeiro. Departamento de Genética. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Epidemiologia de Malformações Congênitas. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Câncer. Divisão de Genética. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Departamento de Genética. Rio de Janeiro, RJ, Brasil.Hospital Universitario La Paz. Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ. Section of Functional and Structural Genomics. Madrid, Spain / CIBERER. Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.Wilms tumor (WT), the most common cancer of the kidney in infants and children, has a complex etiology that is still poorly understood. Identification of genomic copy number variants (CNV) in tumor genomes provides a better understanding of cancer development which may be useful for diagnosis and therapeutic targets. In paired blood and tumor DNA samples from 14 patients with sporadic WT, analyzed by aCGH, 22% of chromosome abnormalities were novel. All constitutional alterations identified in blood were segmental (in 28.6% of patients) and were also present in the paired tumor samples. Two segmental gains (2p21 and 20q13.3) and one loss (19q13.31) present in blood had not been previously described in WT. We also describe, for the first time, a small, constitutive partial gain of 3p22.1 comprising 2 exons of CTNNB1, a gene associated to WT. Among somatic alterations, novel structural chromosomal abnormalities were found, like gain of 19p13.3 and 20p12.3, and losses of 2p16.1-p15, 4q32.5-q35.1, 4q35.2-q28.1 and 19p13.3. Candidate genes included in these regions might be constitutively (SIX3, SALL4) or somatically (NEK1, PIAS4, BMP2) operational in the development and progression of WT. To our knowledge this is the first report of CNV in paired blood and tumor samples in sporadic WT

Novel constitutive CNV detected in Wilms Tumor.

<p>Schematic representation of CNVs detected in both blood and tissue by aCGH. Duplications (blue bars): 2p21 including <i>SIX3</i>, 3p22.1 with <i>CTNNB1</i>, 4p16.3 with <i>FGFR3</i>, and 20q13.3 with <i>SALL4</i>. Deletion (red bar): 19q13.31 including <i>ZNF227</i>, <i>ZNF233</i> and <i>ZNF235</i>. All the alterations were also detected in matched tumor samples.</p

CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype

[Purpose]: CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized overgrowth. Here we tested the hypothesis that, although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.[Methods]: We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from 9 patients using high-throughput, deep sequencing.[Results]: We identified five activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.[Conclusion]: We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.This research was supported by the project “Genetics of vascular and lymphatic malformations” financed with funds donated by Asociación Ultrafondo and Villareal FC, cofinanced by project IP-17 from the funding call “Todos Somos Raros” (Telemaraton TVE promoted by Fundación Isabel Gemio, Federación ASEM, and Federación Española de Enfermedades Raras), cofinanced by the Instituto de Salud Carlos III, FEDER FUNDS FIS PI15/01481, and IIS-Fundación Jiménez Díaz UAM Genome Medicine Chair.Peer reviewe

VizieR Online Data Catalog: Stellar kinematics in CALIFA survey (Falcon-Barroso+, 2017)

This study is based on observations of 300 galaxies drawn from the CALIFA mother and extended samples1, which are part of the photometric catalog of the seventh data release (Abazajian et al., 2009ApJS..182..543A) of the Sloan Digital Sky Survey (SDSS). (1 data file)