In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic

Hereditary hearing loss (HHL) is the most common sensory disorder affecting 1 in 500 newborn children. Since HHL is related to more than 150 target genes, we designed a diagnosis strategy in order to identify pathogenic variants.A total of 1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing, genotyping 25% of them. From undiagnosed patients, 29 families were selected to perform Whole exome sequencing. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG Standards.Some of the novel variants were further studied in silico by structural and stability studies of the mutated proteins. In addition, datasets from deafness and specific variant databases were correlated with different protein motifs in order to predict the theoretical pathogenicity effect of the aminoacid changes. Furthermore, knock-down phenotype rescue assays in zebrafish are underway to accomplish in vivo validation. In some cases, extensive analysis reinforced the pathogenicity prediction effect of variants and surprisingly, in one case, discouraged the deleterious effect of a genetic variant to the protein.Preliminary results in zebrafish confirmed the pathogenicity of one novel variant in the hair cell function and auditory system.This study shows that our algorithm is successful for the genetic diagnosis of deafness. Comprehensive analysis is crucial to strengthen prediction of variant pathogenicity. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of HHL.Fil: Buonfiglio, Paula Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bruque, Carlos David. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; ArgentinaFil: Goldschmidt, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Menazzi, Sebastián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Paoli, Bibiana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Dalamon, Viviana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina53rd European Society of Human Genetics ConferenceVienaAustriaEuropean Society of Human Genetic

Directed paths on hierarchical lattices with random sign weights

We study sums of directed paths on a hierarchical lattice where each bond has either a positive or negative sign with a probability $p$. Such path sums $J$ have been used to model interference effects by hopping electrons in the strongly localized regime. The advantage of hierarchical lattices is that they include path crossings, ignored by mean field approaches, while still permitting analytical treatment. Here, we perform a scaling analysis of the controversial ``sign transition'' using Monte Carlo sampling, and conclude that the transition exists and is second order. Furthermore, we make use of exact moment recursion relations to find that the moments always determine, uniquely, the probability distribution $P(J)$. We also derive, exactly, the moment behavior as a function of $p$ in the thermodynamic limit. Extrapolations ($n\to 0$) to obtain for odd and even moments yield a new signal for the transition that coincides with Monte Carlo simulations. Analysis of high moments yield interesting ``solitonic'' structures that propagate as a function of $p$. Finally, we derive the exact probability distribution for path sums $J$ up to length L=64 for all sign probabilities.Comment: 20 pages, 12 figure

Phenotypic variability in 47, XXX patients. Clinical report of four new cases

Fil: Goldschmidt, Ernesto. CEGIN. Asesoramiento genético integral; Argentina.Fil: Márquez, Marisa. CEGIN. Asesoramiento genético integral; Argentina.Fil: Solari, Andrea. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Ziembar, María I. CEGIN. Asesoramiento genético integral; Argentina.Fil: Laudicina, Alejandro. CEGIN. Asesoramiento genético integral; Argentina.El síndrome 47, XXX se debe a un cromosoma extra del par sexual; su incidencia es de 1 en 1000 recién nacidas vivas. Sin embargo, este síndrome no suele sospecharse al nacimiento ni en la infancia. Muchas de estas pacientes son diagnosticadas durante la edad adulta por falla ovárica precoz o esterilidad, debido a la falta de características clínicas específicas. Este trabajo describe cuatro casos de pacientes 47, XXX y su variabilidad fenotípica

Phenotypic variability in 47, XXX patients. Clinical report of four new cases

Fil: Goldschmidt, Ernesto. CEGIN. Asesoramiento genético integral; Argentina.Fil: Márquez, Marisa. CEGIN. Asesoramiento genético integral; Argentina.Fil: Solari, Andrea. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Ziembar, María I. CEGIN. Asesoramiento genético integral; Argentina.Fil: Laudicina, Alejandro. CEGIN. Asesoramiento genético integral; Argentina.El síndrome 47, XXX se debe a un cromosoma extra del par sexual; su incidencia es de 1 en 1000 recién nacidas vivas. Sin embargo, este síndrome no suele sospecharse al nacimiento ni en la infancia. Muchas de estas pacientes son diagnosticadas durante la edad adulta por falla ovárica precoz o esterilidad, debido a la falta de características clínicas específicas. Este trabajo describe cuatro casos de pacientes 47, XXX y su variabilidad fenotípica

Predictive value of the CLL-IPI in CLL patients receiving chemo-immunotherapy as first-line treatment

An international collaboration has led to the development of a comprehensive tool [CLL\u2010IPI international prognostic index for CLL] for the predicting of overall survival (OS) in chronic lymphocytic leukemia (CLL).1 CLL\u2010IPI was based on data collected from 3500 CLL patients and was based on the following parameters: TP53 deletion and/or mutation, IGHV mutational status, \u3b22\u2010microglobulin plasma levels, clinical stage, and age. CLL\u2010IPI provides the means to stratify CLL patients in the daily clinical practice (Table S1).1 Although validated for OS2-4 and time to first treatment (TTFT),5 the predictive value of CLL\u2010IPI on progression\u2010free survival (PFS) has until now only been demonstrated in a single study on patients treated with chlorambucil (CLB), as monotherapy, or in combination with obinutuzumab or rituximab, as a first\u2010line approach (CLL11 study),6 and presented as a poster at the annual meeting of the American Society of Hematology (ASH) in 2016

Predictive value of the CLL-IPI in CLL patients receiving chemo-immunotherapy as first-line treatment

An international collaboration has led to the development of a comprehensive tool [CLL-IPI international prognostic index for CLL] for the predicting of overall survival (OS) in chronic lymphocytic leukemia (CLL).1 CLL-IPI was based on data collected from 3500 CLL patients and was based on the following parameters: TP53 deletion and/or mutation, IGHV mutational status, \u3b22-microglobulin plasma levels, clinical stage, and age. CLL-IPI provides the means to stratify CLL patients in the daily clinical practice (Supplementary Table 1).1 Although validated for OS2-4 and time to first treatment (TTFT),5 the predictive value of CLL-IPI on progression-free survival (PFS) has until now only been demonstrated in a single study on patients treated with chlorambucil (CLB), as monotherapy, or in combination with obinutuzumab or rituximab, as a first-line approach (CLL11 study),6 and presented as a poster at the annual meeting of the American Society of Hematology (ASH) in 2016. This article is protected by copyright. All rights reserved