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1. Tip of the iceberg: a tertiary care centre retrospective study of left ventricular hypertrophy aetiologies

Author

Didier Carrié, Stéphanie Brun, Eve Cariou, Michel Galinier, Maxime Beneyto, Jérémy Brunel, Alex Scripcariu, Hubert Delasnerie, and Delphine Dupin Deguine

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Aims To phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT).Methods and results Consecutive patients referred for aetiological workup of LVH, beginning at 12 mm of LVWT were retrospectively included in this tertiary single-centred observational study. Patients presenting with severe aortic stenosis were excluded. Aetiological workup was reviewed for each subject and aetiologies were adjudicated by expert consensus.Among 591 patients referred for LVH aetiological workup, 41% had a maximal LVWT below 15 mm. LVH aetiologies were led by cardiac amyloidosis (CA, 34.3%), followed by sarcomeric hypertrophic cardiomyopathy (S-HCM, 32.1%), hypertensive cardiomyopathy (21.7%), unknown aetiology (7.6%) and other (4.2%), including Anderson-Fabry’s disease (1.7%). CA and S-HCM affected over 50% of patients with mild LVH (12–14 mm); the prevalence of these aetiologies rose with LVH severity. Among patients with Anderson-Fabry’s disease, 4 (40%) had a maximal LVWT

Published
2021
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2. First evidence of <scp> SOX2 </scp> mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

Author

Bertrand Chesneau, Marion Aubert‐Mucca, Félix Fremont, Jacmine Pechmeja, Vincent Soler, Bertrand Isidor, Mathilde Nizon, Hélène Dollfus, Josseline Kaplan, Lucas Fares‐Taie, Jean‐Michel Rozet, Tiffany Busa, Didier Lacombe, Sophie Naudion, Jeanne Amiel, Marlène Rio, Tania Attie‐Bitach, Cécile Lesage, Dominique Thouvenin, Sylvie Odent, Godelieve Morel, Catherine Vincent‐Delorme, Odile Boute, Clémence Vanlerberghe, Anne Dieux, Simon Boussion, Laurence Faivre, Lucile Pinson, Fanny Laffargue, Gwenaël Le Guyader, Guylène Le Meur, Fabienne Prieur, Victor Lambert, Beatrice Laudier, Edouard Cottereau, Carmen Ayuso, Marta Corton‐Pérez, Laurence Bouneau, Cédric Le Caignec, Véronique Gaston, Claire Jeanton‐Scaramouche, Delphine Dupin‐Deguine, Patrick Calvas, Nicolas Chassaing, Julie Plaisancié, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Jeunes Aveugles [Toulouse] (IJA), Clinique rive gauche, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Lille, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional d'Orléans (CHRO), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid (UAM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), French National Research AgencyFrench National Research Agency (ANR) [ANR-10-COHO-0003], and ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010)

Subjects
Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA Copy Number Variations, SOXB1 Transcription Factors, Peters' anomaly, [SDV]Life Sciences [q-bio], CNV, SOX2, eye diseases, PAX6, Corneal Opacity, microphthalmia, Anterior Eye Segment, Mutation, B3GLCT, Genetics, Humans, anterior segment dysgenesis, FOXE3, Eye Abnormalities, PITX3, Genetics (clinical)
Abstract

International audience; Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

Published
2022
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3. The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

Author

Roux, Luke Mansard, David Baux, Christel Vaché, Catherine Blanchet, Isabelle Meunier, Marjolaine Willems, Valérie Faugère, Corinne Baudoin, Melody Moclyn, Julie Bianchi, Helene Dollfus, Brigitte Gilbert-Dussardier, Delphine Dupin-Deguine, Dominique Bonneau, Isabelle Drumare, Sylvie Odent, Xavier Zanlonghi, Mireille Claustres, Michel Koenig, Vasiliki Kalatzis, and Anne-Françoise

Subjects
Usher syndrome, retinitis pigmentosa, hearing loss, MYO7A, USH2A, pathogenic genotype, ACMG classification, deep intronic variant, otorhinolaryngologic diseases
Abstract

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic MYO7A and USH2A genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in USH2A. Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed.

Published
2021
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4. Tip of the iceberg: a tertiary care centre retrospective study of left ventricular hypertrophy aetiologies

Author

Maxime Beneyto, Olivier Lairez, Didier Carrié, Delphine Dupin Deguine, Hubert Delasnerie, Jérémy Brunel, Yoan Lavie-Badie, Eve Cariou, S. Brun, Alex Scripcariu, and Michel Galinier

Subjects
Male, cardiomyopathies, medicine.medical_specialty, Heart Ventricles, Cardiomyopathy, Magnetic Resonance Imaging, Cine, hypertrophic, 030204 cardiovascular system & hematology, Left ventricular hypertrophy, Ventricular Function, Left, Tertiary Care Centers, 03 medical and health sciences, 0302 clinical medicine, genetic diseases, Internal medicine, Epidemiology, Diseases of the circulatory (Cardiovascular) system, Medicine, Humans, 030212 general & internal medicine, cardiovascular diseases, Heart Failure and Cardiomyopathies, Aged, Retrospective Studies, business.industry, Hypertrophic cardiomyopathy, Retrospective cohort study, Middle Aged, medicine.disease, Stenosis, Cardiac amyloidosis, Echocardiography, RC666-701, Etiology, Cardiology, inborn, Female, Hypertrophy, Left Ventricular, epidemiology, Cardiology and Cardiovascular Medicine, business, cardiomyopathy
Abstract

AimsTo phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT).Methods and resultsConsecutive patients referred for aetiological workup of LVH, beginning at 12 mm of LVWT were retrospectively included in this tertiary single-centred observational study. Patients presenting with severe aortic stenosis were excluded. Aetiological workup was reviewed for each subject and aetiologies were adjudicated by expert consensus.Among 591 patients referred for LVH aetiological workup, 41% had a maximal LVWT below 15 mm. LVH aetiologies were led by cardiac amyloidosis (CA, 34.3%), followed by sarcomeric hypertrophic cardiomyopathy (S-HCM, 32.1%), hypertensive cardiomyopathy (21.7%), unknown aetiology (7.6%) and other (4.2%), including Anderson-Fabry’s disease (1.7%). CA and S-HCM affected over 50% of patients with mild LVH (12–14 mm); the prevalence of these aetiologies rose with LVH severity. Among patients with Anderson-Fabry’s disease, 4 (40%) had a maximal LVWT ConclusionsMild LVH (ie, 12–14 mm) conceals multiple aetiologies that can lead to specific treatment, cascade family screening and specific follow-up. Overall, CA is nowadays the leading cause of LVH in tertiary centers.

Published
2020

5. Psychosocial Impact of Predictive Genetic Testing in Hereditary Heart Diseases: The PREDICT Study

Author

Elise Schaefer, Delphine Dupin Deguine, C. Rouzier, Estelle Gandjbakhch, Krystelle Séné, Claire Cécile Michon, Marie Lise Babonneau, Philippe Charron, Caroline Sawka, Bertrand Isidor, Jean François Pruny, Mélanie Hebert, Stéphanie Staraci, Isabelle Denjoy, Caroline Rooryck-Thambo, Ibticem Raji, Rafik Mansouri, Aurélien Palmyre, Linda Akloul, Sandrine Brice, Annick Toutain, Sophie Tezenas du Montcel, Angelique Curjol, Carole Maupain, Gipsy Billy, Céline Bordet, Alexandre Moerman, Pascale Richard, Marcela Gargiulo, Véronique Fressart, Elsa Le Boette, Flavie Ader, Bruno Leheup, Marc Planes, Karine Nguyen, A.C. Brehin, Jean Michael Mazzella, Amine Bekhechi, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHU Pitié-Salpêtrière], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Ambroise Paré [AP-HP], Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, CHU Pontchaillou [Rennes], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), CHU Rouen, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], CHU Strasbourg, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pointe-à-Pitre/Abymes [Guadeloupe], CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU de Saint-Brieuc, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Paris - UFR Pharmacie [Santé] (UP UFR Pharmacie), Université de Paris (UP), Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Nice Sophia Antipolis (1965 - 2019) (UNS), UFR Pharmacie [Santé] - Université Paris Cité (UFR Pharmacie UPCité), and Université Paris Cité (UPCité)

Subjects
0301 basic medicine, cardiomyopathies, medicine.medical_specialty, lcsh:Medicine, 030204 cardiovascular system & hematology, 030105 genetics & heredity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, History of depression, Medicine, Prospective cohort study, predictive genetic testing, Genetic testing, hereditary heart diseases, medicine.diagnostic_test, business.industry, lcsh:R, distress, Retrospective cohort study, social, General Medicine, anxiety, Family life, 3. Good health, Distress, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Anxiety, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, psychological, medicine.symptom, business, Psychosocial
Abstract

Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety Inventory) in 517 adults, administered three times to the prospective cohort (PCo: n = 264) and once to the retrospective cohort (RCo: n = 253). The main motivations for undergoing PGT were &ldquo, to remove doubt&rdquo, and &ldquo, for their children&rdquo, The level of anxiety increased between pre-test and result appointments (p &lt, 0.0001), returned to baseline after the result (PCo), and was moderately elevated at 4.4 years (RCo). Subjects with a history of depression or with high baseline anxiety were more likely to develop anxiety after PGT result (p = 0.004 and p &lt, 0.0001, respectively), whatever it was. Unfavourable changes in professional and/or family life were observed in 12.4% (PCo) and 18.7% (RCo) of subjects. Few regrets about PGT were expressed (0.8% RCo, 2.3% PCo). Medical benefit was not the main motivation, which emphasises the role of pre/post-test counselling. When PGT was performed by expert teams, the negative impact was modest, but careful management is required in specific categories of subjects, whatever the genetic test result.

Published
2020
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6. P1247FLNC pathogenic variants in patients with various cardiomyopathies:prevalence and genotype-phenotype correlations

Author

P. Charron, Y. Troadec, Flavie Ader, Laurent Gouya, Eric Villard, Xavier Jeunemaitre, P. Richard, M. Mathieu Dramard, Diala Khraiche, Delphine Dupin-Deguine, P. De Groote, L. Van Maldergem, Jean François Pruny, P. Reant, and Caroline Rambaud

Subjects
Genetics, business.industry, Medicine, In patient, Cardiology and Cardiovascular Medicine, business, Genotype-Phenotype Correlations
Abstract

Background/Introduction Pathogenic variants FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes.However, few data on phenotype-genotype correlation are available. Purpose Our aim was to estimate the prevalence of FLNC pathogenic variants in cardiomyopathies and to study the relations between phenotype and genotype. Methods DNAs from a cohort of 1150 unrelated index-patients with an isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 52 cardiomyopathy disease-causing genes. Results A FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1 to 8% depending on the cardiomyopathy subtypes. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame variants were found in other phenotypes. This work reported for the first time a left ventricular non-compaction associated with FLNC pathogenic variant. In the cohort, nine patients (32%) were implanted with an automatic defibrillator. In 7 families (25%), history of sudden cardiac death (SCD) before 50 years was reported. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (p=0.01). Four patients died of cardiac cause including 3 from SCD and 1 from heart failure. Conclusion This work highlights the role of FLNC in cardiomyopathies. A correlation between the type of the variant and the cardiomyopathy subtype was observed as well as with SCD risk. These new data should be taken into consideration for patient's management and primary prevention of sudden cardiac death. Acknowledgement/Funding La ligue contre la Cardiomyopathie

Published
2019
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7. Chest pain in Brugada syndrome: Prevalence, correlations, and prognosis role

Author

Michel Galinier, Michel Haïssaguerre, Benjamin Monteil, Delphine Dupin-Deguine, Didier Carrié, Frederic Sacher, Quentin Voglimacci-Stephanopoli, Franck Mandel, Anne Rollin, Mélèze Hocini, Philippe Maury, Eric Bieth, Pierre Mondoly, and Fatiha Sebai

Subjects
Adult, Male, medicine.medical_specialty, Chest Pain, Coronary Vasospasm, Coronary Artery Disease, 030204 cardiovascular system & hematology, Chest pain, Sudden death, Sudden cardiac death, Angina Pectoris, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Prevalence, Humans, 030212 general & internal medicine, Correlation of Data, Brugada syndrome, Brugada Syndrome, Retrospective Studies, Univariate analysis, business.industry, ST elevation, fungi, Atrial fibrillation, General Medicine, Middle Aged, medicine.disease, Prognosis, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract

Background Brugada syndrome (BrS) is sometimes diagnosed because of chest pain. Prevalence and characteristics of such BrS patients are unknown. Methods A total of 200 BrS probands were retrospectively included. BrS diagnosis made because of chest pain (n = 34, 17%) was compared to the other ones. Results BrS probands with diagnosis because of chest pain had significantly more often smoker habits, increased body mass index, and familial history of coronary artery disease but less frequently previous resuscitated sudden death/syncope or atrial fibrillation. Presence of coronary spasm and familial coronary artery disease were independently associated with BrS diagnosed because of chest pain. They presented more often with spontaneous type 1 ST elevation (59% vs 26%, P = .0004) and higher ST elevation during the episode of chest pain compared to other patients or compared to baseline electrocardiogram after chest pain resumption. ST elevation during chest pain was lower compared to ajmaline test. A total of 20% of them had significant coronary artery disease and four (11%) had coronary spasm, and they experienced more often recurrent chest pain episodes (24% vs 5%, P = .0002). Presence of chest pain at BrS diagnosis was not correlated to future arrhythmic events in univariate analysis. Only previous sudden cardiac death (SD)/syncope and familial SD were still significantly associated with outcome in multivariate analysis. Conclusion Chest pain is a common cause for BrS diagnosis, although major part is not apparently explained by ischemic heart disease. Mechanisms leading to chest main remain unknown in the other ones. ST elevation is higher in this situation but does not seem to carry poor prognosis.

Published
2019

8. Author response for 'FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations'

Author

Laurent Gouya, Flavie Ader, Michèle Mathieu Dramard, Albert A. Hagège, Delphine Dupin-Deguine, Y. Troadec, Jean François Pruny, P. Reant, Caroline Rooryck-Thambo, Lionel Van Maldergem, Claire Perret, Caroline Rambaud, Eric Villard, Pascal de Groote, Philippe Charron, Marion Gérard, Diala Khraiche, P Richard, and Xavier Jeunemaitre

Subjects
Genetics, In patient, FLNC, Biology, Genotype-Phenotype Correlations
Published
2019
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9. Searching for secondary findings: considering actionability and preserving the right not to know

Author

Delphine Dupin-Deguine, Jean-Paul Bonnefont, Catherine Bourgain, Bertrand Isidor, Paul-Loup Weil-Dubuc, Julie Plaisancié, Franck Bourdeaut, Eric Bieth, Laurent Pasquier, Nicolas Chassaing, Kym M. Boycott, Sophie Julia, Benjamin Cogné, Nadège Corradini, Pascale Saugier-Veber, Delphine Héron, Arnold Munnich, Damien Haye, Marie Vincent, Mathilde Nizon, Mauro Turrini, Sylvie Manouvrier, Stéphane Bézieau, Patrick Calvas, Cyril Mignot, Danya F. Vears, PORCHET, Nathalie, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Excellence Laboratory LabEx DISTALZ, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Pédiatrique [CHU Nantes], Hôpital Mère-Enfant, CHU de Nantes, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], University of Ottawa [Ottawa], Université Paris 1 Panthéon-Sorbonne - UFR Philosophie (UP1 UFR10), Université Paris 1 Panthéon-Sorbonne (UP1), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Melbourne, Murdoch Children's Research Institute (MCRI), Laboratoire de Génétique Moléculaire, CHU Toulouse [Toulouse], Département de Génétique (CHU Necker - Enfants Malades [AP-HP] ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service de génétique médicale, Service de génétique clinique, hôpital Sud, Groupe de recherche clinique 'déficience intellectuelle et autisme', and Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Genetics, Medical, [SDV]Life Sciences [q-bio], MEDLINE, Truth Disclosure, 03 medical and health sciences, Viewpoint, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Genetics (clinical), Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Information retrieval, Genome, Human, 030305 genetics & heredity, Genomics, 16. Peace & justice, Europe, [SDV] Life Sciences [q-bio], Practice Guidelines as Topic, Psychology, Medical ethics
Abstract

International audience; No abstract available

Published
2019
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10. Pattern of myocardial

Author

Sarah, Pradel, Stéphanie, Brun, Gérard, Victor, Pierre, Pascal, Pauline, Fournier, David, Ribes, Yoan, Lavie-Badie, Michel, Galinier, Didier, Carrié, Isabelle, Berry, Olivier, Lairez, and Delphine, Dupin-Deguine

Subjects
Aged, 80 and over, Male, Tomography, Emission-Computed, Single-Photon, Amyloid Neuropathies, Familial, Heart Diseases, Myocardium, Stroke Volume, Technetium Tc 99m Medronate, Ventricular Function, Left, Cohort Studies, Humans, Female, Radiopharmaceuticals, Aged
Abstract

The purpose of the study was to describe the pattern ofFifty patients with TTR-CA underwentThe mean population age was 79 ± 10 years. Mean H/WB ratio was 12 ± 7. MyocardialThese findings show the relationship between bone tracer myocardial uptake and LV functions in patients with TTR cardiac amyloidosis.

Published
2018

11. FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases

Author

Floriane Petit, Agnès Delahodde, Cécile Masson, Christine Bole-Feysot, Anthony Drecourt, Fanny Mochel, Christelle Domange, Souad Gherbi, Josseline Kaplan, Sylvie Gerber, Delphine Dupin Deguine, Olivier Sterkers, Georges Challe, Crystel Bonnet, Myriam Oufadem, Laurence Jonard, Oriane Mercati, Laurence Mahieu, Agnès Rötig, Patrick Nitschke, Saber Masmoudi, Stanislas Lyonnet, Isabelle Mosnier, Didier Bouccara, Antoine Paul, Sandrine Marlin, Christelle Vasnier, Ines Ben Aissa, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Iron-Sulfur Proteins, Male, Mitochondrial Diseases, Fe-S cluster synthesis, [SDV]Life Sciences [q-bio], Mutant, Auditory neuropathy, 030105 genetics & heredity, chemistry.chemical_compound, iron-sulfur cluster, Gene expression, Hearing Loss, Central, Genetics (clinical), Genetics, Mitochondria, Pedigree, Complementation, Ferredoxin-NADP Reductase, FDXR, Child, Preschool, Female, inorganic chemicals, Adult, Saccharomyces cerevisiae Proteins, Adolescent, Mitochondrial disease, Iron, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, Young Adult, Atrophy, Biosynthesis, ARH1, Report, medicine, Humans, Amino Acid Sequence, iron overload, Genetic Complementation Test, DNA replication, medicine.disease, Optic Atrophy, 030104 developmental biology, chemistry, Mutation, Sequence Alignment
Abstract

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.

Published
2017
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12. A Second Observation of the Rare Frameshift Mutation in the β-Globin Gene: Codon 46 (+A) (Hbb:c.138_139insA)

Author

Elyes Slim Ghedira, Delphine Dupin-Deguine, Denis Duffilot, Nathalie Lemetayer, Emmanuelle Faubert, and Serge Pissard

Subjects
Adult, Male, Proband, Clinical Biochemistry, Buccal swab, Nonsense mutation, beta-Globins, Biology, medicine.disease_cause, Compound heterozygosity, Frameshift mutation, Exon, medicine, Humans, Point Mutation, Missense mutation, Family, Child, Codon, Frameshift Mutation, Genetics (clinical), Genetics, Mutation, Base Sequence, beta-Thalassemia, Biochemistry (medical), Hematology, Middle Aged, Molecular biology, Pedigree, Mutagenesis, Insertional, Female
Abstract

The preparation of a prenatal diagnosis in a family of North-African origin in which a child received a bone marrow transplant for β-thalassemia major (β-TM), prompted us to make the molecular diagnosis in the parents and siblings. Molecular and phenotype assays were carried on blood samples from the parents and the proband's sister. The father, a 45-year-old man, was found to be heterozygous for a rare mutation in exon 2 [codon 46 (+A), HBB:c.138_139insA] creating a frameshift, while the mother and sister were found to be carriers of the common codon 39 (CT) stop mutation (HBB:c.118CT). Because of the bone marrow transplant, proband genotyping was done from a buccal swab and revealed that he is a compound heterozygote for both the codon 46 and codon 39 mutations. In the parents and sister, hematological parameters were those of a thalassemia minor in agreement with the two β(0) mutations found in the family.

Published
2011
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13. The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Author

Albert David, Chloé Quélin, Clarisse Baumann-Morel, Eric Bieth, Bruno Dumont, Judith Melki, Elise Shaeffer, Yves Alembik, Fabienne Giuliano, Christel Thauvin, Nicolas Chassaing, Sophie Julia, Anne-Lise Delezoide, Marine Lebrun, Tiffany Busa, Geneviève Baujat, David Geneviève, Séverine Audebert, Yline Capri, Patricia Blanchet, Martine Le Merrer, Sandrine Marlin, Mouna Barat-Houari, Marianne Till, Nicole Philip, Laurence Faivre, Patrick Calvas, Karine Nguyen, Alice Masurel, Vidrica Ciorca, François Cartault, Jacqueline Vigneron, Alice Goldenberg, Jelena Martinovic, Monique Mozelle-Nivoix, Renaud Touraine, Ghislaine Plessis, Marie-Line Jacquemont, Jean-Luc Alessandri, Delphine Dupin-Deguine, Valérie Cormier-Daire, Aurélie Fabre, Jeanne Amiel, Marie Brechard, Bertrand Isidor, Salima El Chehadeh, Sylvie Odent, Isabelle Touitou, Josseline Kaplan, Dominique Martin-Coignard, Lucile Pinson, Sabine Sigaudy, Christine Coubes, Didier Lacombe, Frédéric Tm Them, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU La Réunion], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Biologie du Développement, Service de génétique médicale, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital l'Archet, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service de Genetique, Service de Génétique Clinique, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CH Le Mans, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), CHU Caen-Hôpital Clémenceau, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
0301 basic medicine, Proband, Male, Candidate gene, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], Biology, Osteochondrodysplasias, Article, 03 medical and health sciences, symbols.namesake, Kniest dysplasia, Protein Domains, Genetics, medicine, Humans, Connective Tissue Diseases, Collagen Type II, Genetics (clinical), Sanger sequencing, [ SDV ] Life Sciences [q-bio], Arthritis, Collagen Diseases, Retinal Detachment, medicine.disease, Phenotype, Human genetics, 3. Good health, Pedigree, 030104 developmental biology, Amino Acid Substitution, Dysplasia, Spondyloepiphyseal dysplasia congenita, symbols, Female
Abstract

International audience; Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.European Journal of Human Genetics advance online publication, 2 December 2015; doi:10.1038/ejhg.2015.250

Published
2016
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14. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness

Author

Jean-Pierre Hardelin, Jacques Young, Sandrine Marlin, Christine Francannet, Chrystel Leroy, Jérôme Bertherat, Virginie Bodereau, O. Verier-Mine, Delphine Dupin-Deguine, F. Archambeaud, Viviane Baral, Séverine Marcos, François-Joseph Kurtz, Michel Goossens, Catherine Dodé, Asma Chaoui, Veronique Pingault, Yuli Watanabe, Corinne Fouveaut, Nadege Bondurand, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biochimie et Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'endocrinologie, Centre Hospitalier de Valenciennes, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Service de pédiatrie, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville)-Hôpital Bel Air, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence pour les Maladies Rares, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Institut de la Santé et de la Recherche Médicale (Inserm) and the Agence Nationale de la Recherche (ANR-JCJC-2010 to NB and ANR-2009-GENOPAT-017 to CD). AC is a recipient of a fellowship from the Fondation pour la Recherche Médicale (FRM). SM is receiving a salary on theANR-2009-GENOPAT-017 grant., Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], CHU - HÔTEL-DIEU Clermont-Ferrand, Hôpital Bel Air-Centre hospitalier régional Metz-Thionville ( CHR Metz-Thionville ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares, Génétique et physiologie de l'audition, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Bel Air-Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges

Subjects
Olfactory system, Male, medicine.medical_specialty, Indoles, Kallmann syndrome, SOX10, DNA Mutational Analysis, Anosmia, Biology, Deafness, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Olfactory nerve, Hypogonadotropic hypogonadism, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, Humans, Genetics(clinical), Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Waardenburg syndrome, SOXE Transcription Factors, Galactosides, Kallmann Syndrome, Olfactory Pathways, medicine.disease, Endocrinology, Mutation, embryonic structures, Female, Olfactory ensheathing glia, France, medicine.symptom, Neuroglia, 030217 neurology & neurosurgery, HeLa Cells, Plasmids
Abstract

International audience; Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.

Published
2013
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15. Improving genetic testing pathways for transthyretin amyloidosis in France: challenges and strategies

Author

Bérénice Hebrard, Marie-Lise Babonneau, Philippe Charron, Emilie Consolino, Benjamin Dauriat, Delphine Dupin-Deguine, Dominique Fargeaud, Agnès Farrugia, Anna-Gaëlle Giguet-Valard, Damien Guijarro, Jocelyn Inamo, Julien Jeanneteau, Jean-Michaël Mazzella, Claire-Cécile Michon, Gilles Millat, Frédéric Mouquet, Silvia Oghina, Yann Pereon, Vianney Poinsignon, Julie Pompougnac, Julie Proukhnitzky, Elise Schaefer, Franck Sturtz, Mathilde Trosdorf, Anne Auguste, Giorgia Canali, Alexandre Combes, Benoît Funalot, and Thibaud Damy

Subjects
ATTR, Genetic testing, Rare disease, Multidisciplinary expert group, Experts’ consensus, Medicine
Abstract

Abstract Transthyretin amyloidosis (ATTR) is a severe and rare disease characterized by the progressive deposition of misfolded transthyretin proteins, causing irreversible organ damage. Transthyretin amyloidosis can present as a hereditary ATTR or acquired wild-type ATTR form. Genetic testing is critical for determining a hereditary predisposition and subsequently initiating appropriate family screening. In France, strict regulations govern genetic testing that aim to protect patients and their families affected by hereditary diseases such as ATTR. However, challenges persist in establishing an effective genetic testing pathway. A multidisciplinary group of French experts convened to discuss the challenges associated with an ATTR genetic diagnosis and to propose improvement strategies. Key challenges include the lack of pathway standardization, communication gaps between healthcare professionals (HCPs) and patients, and difficulties in complying with regulatory requirements. Concerns about patient data safety and outsourced testing quality further complicate matters. Proposed strategies included the development of stakeholder mapping tools for HCPs and patients, educational programs to improve literacy on genetic testing regulations, increase disease awareness among medical geneticists and genetic counselors, and strengthening HCP-patient communication through educational materials. These initiatives aim to streamline the genetic testing pathway, enhance compliance with regulations, and ultimately provide optimal support for patients and families with ATTR.

Published
2024
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16. Value of natriuretic peptides and tissue Doppler imaging in the estimation of left ventricular filling pressure in patients with cardiac amyloidosis

Author

Didier Carrié, Stéphanie Brun, Eve Cariou, Pauline Fournier, David Ribes, Stanislas Faguer, Antoine Huart, Michel Galinier, Daniel Adoue, Laurent Alric, Léonardo Astudillo, Pauline Bernadet Monrozies, Dominique Chauveau, Pascal Cintas, Magali Colombat, Audrey Delas, Delphine Dupin-Deguine, Joelle Guitard, Bénédicte Puissant, Grégory Pugnet, Grégoire Prévot, Murielle Roussel, and Laurent Sailler

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Estimation of left ventricular filling pressures (LVFP) is a determining factor in the follow-up of patients with cardiac amyloidosis (CA). Natriuretic peptides (NPs) and tissue Doppler imaging may be used to monitor LVFP in patients with CA. The aim of this study was to evaluate the value of NPs and Doppler parameters in estimating LVFP in patients with CA.Methods Fifty patients with biopsy-verified light chain (n=31), A protein amyloidosis (AA) (n=1), apoliporotein A2 (n=1) or bone scintigraphy-proven transthyretin (n=17) CA were retrospectively included. All patients underwent right heart catheterisation (RHC). Among them, 48 (96%) and 43 (86%) had assays of NPs (20 brain natriuretic peptide (BNP), 27 N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) and 1 both) and transthoracic echocardiography performed within 24 hours of RHC, respectively.Results The median BNP and NT-proBNP levels were 1000 (243–1477) ng/L and 10 106 (2935–13 348) ng/L, respectively. Echocardiography demonstrated left atrial enlargement with a mean volume of 47±16 mL and low tissue Doppler lateral Ea of 5±2 cm/s. The mean early diastolic mitral inflow velocity on early lateral mitral annular diastolic velocity ratio (E/Ea) ratio was 18±7, and the mean pulmonary capillary wedge pressure (PCWP) by RHC was 18±8 mm Hg. There was no correlation between BNP (r=0.260, p=0.774) or NT-proBNP (r=−0.103, p=0.984) levels and PCWP. There was a slight correlation between E/Ea ratio and PCWP (r=0.337, p=0.029). E/Ea ratio >14 performed poorly in differentiating elevated and low LVFP.Conclusion In patients with CA, NPs do not accurately estimate PCWP. Tissue Doppler-derived mitral E/Ea ratio is correlated with PCWP, but the slight correlation requires to estimate LVFP in a broad clinical and imaging context to avoid diagnostic errors.

Published
2019
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