Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment

Noonan syndrome; Genetic; Growth hormoneSíndrome de Noonan; Genético; Hormona del crecimientoSíndrome de Noonan; Genètica; Hormona del creixementMolecular study has become an invaluable tool in the field of RASopathies. Treatment with recombinant human growth hormone is approved in Noonan syndrome but not in the other RASopathies. The aim of this study was to learn about the molecular base of a large cohort of patients with RASopathies, with particular emphasis on patients with pathogenic variants in genes other than PTPN11, and its potential impact on rGH treatment indication. We reviewed the clinical diagnosis and molecular findings in 451 patients with a genetically confirmed RASopathy. HRAS alterations were detected in only 2 out of 19 patients referred with a Costello syndrome suspicion, whereas pathogenic variants in RAF1 and SHOC2 were detected in 3 and 2, respectively. In 22 patients referred with a generic suspicion of RASopathy, including cardiofaciocutaneous syndrome, pathogenic alterations in classic Noonan syndrome genes (PTPN11, SOS1, RAF1, LZTR1, and RIT1) were found in 7 patients and pathogenic variants in genes associated with other RASopathies (HRAS, SHOC2, and PPPCB1) in 4. The correct nosological classification of patients with RASopathies is critical to decide whether they are candidates for treatment with rhGH. Our data illustrate the complexity of differential diagnosis in RASopathies, as well as the importance of genetic testing to guide the diagnostic orientation in these patients.This research was partly funded by Fondo de Investigaciones Sanitarias (PI 06/1179), a 2015 José Igea Grant from Fundación de la Sociedad Española de Endocrinología Pediátrica (SEEP), and a Fundación SEEP Prize for the best Oral Communication in the SEEP annual meeting 2010 and 2013. J.L.S. and A.C. received a grant from Instituto de Investigación Sanitaria Gregorio Marañón

L’intelligence comme dispositif de pouvoir

O objetivo do presente estudo, é compreender a inscrição individual e social de discursos usados por alunas, em diferentes posições de classe social, para explicar os seus sucessos académicos. Foram entrevistadas 19 alunas portuguesas do 11º ano de escolaridade provenientes das classes trabalhadora e alta, com elevado rendimento académico. A Análise Foucaudiana do Discurso aponta para a importância da posição de classe na construção dos sujeitos relativamente à sua conceção de inteligência e ao sucesso escolar. A inteligência funciona assim como um dispositivo de poder que regula as relações entre sujeitos de diferentes classes sociais.The objective of the present study is to understand the individual and social inscription of discourses used by students from different social class positions to explain their academic achievement. Nineteen portuguese students, from the 11th grade, with high academic performance and from the working class and upper class, in northern Portugal, were interviewed. Foucauldian Discourse Analysis points to the importance of class position in the construction of the subjects with respect to their concept of intelligence and academic success. Intelligence works as a power device that regulates the relations among subjects of different social classes.L’objectif de cette étude est de comprendre l’inscription individuelle et sociale des discours utilisés par les apprenantes dans différentes positions de classe sociale, pour expliquer leurs succès académiques. Dix-neuf apprenantes portugaises de la 11ème année de scolarité dotées d’un bon rendement scolaire issues des classes ouvrières et moyennes supérieures ont été interviewées. L’Analyse Foucaldienne du Discours souligne l’importance de la position de classe dans la construction des sujets concernant leur conception de l’intelligence et de la réussite scolaire. L’intelligence fonctionne aussi bien en tant que dispositif de pouvoir qui régit les relations entre les individus de différentes classes sociales.(undefined

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

BACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.Instituto de Salud Carlos III [PI11/0699, PI14/0967, PI14/01477, RD012/0042/0029, RD012/0042/0049, RD012/0042/0066, RD12/0042/0069]; Spanish Ministry of Economy and Competitiveness [SAF2015-71863-REDT]; Plan Nacional de I+D+I; Plan Estatalde I+D+I, European Regional Development Fund; Health in Code SLS