Author: "Hélène Dollfus" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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147 results on '"Hélène Dollfus"'

1. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period

Author: Andrea M, Haqq, Wendy K, Chung, Hélène, Dollfus, Robert M, Haws, Gabriel Á, Martos-Moreno, Christine, Poitou, Jack A, Yanovski, Robert S, Mittleman, Guojun, Yuan, Elizabeth, Forsythe, Karine, Clément, and Jesús, Argente
Subjects: Treatment Outcome, Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine, Humans, Receptor, Melanocortin, Type 4, Obesity, Bardet-Biedl Syndrome, Alstrom Syndrome
Abstract: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI97th percentile for age and sex for those aged 6-15 years and ≥30 kg/mBetween Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.Rhythm Pharmaceuticals.
Published: 2022
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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. Retinal Degeneration Animal Models in Bardet-Biedl Syndrome and Related Ciliopathies

Author: Clarisse Delvallée and Hélène Dollfus
Subjects: Polycystic Kidney Diseases, Retinal Degeneration, Macaca mulatta, General Biochemistry, Genetics and Molecular Biology, Mice, Disease Models, Animal, Cytoskeletal Proteins, Animals, Humans, Cilia, Caenorhabditis elegans, Bardet-Biedl Syndrome, Zebrafish, Adaptor Proteins, Signal Transducing
Abstract: Retinal degeneration due to photoreceptor ciliary-related proteins dysfunction accounts for more than 25% of all inherited retinal dystrophies. The cilium, being an evolutionarily conserved and ubiquitous organelle implied in many cellular functions, can be investigated by way of many models from invertebrate models to nonhuman primates, all these models have massively contributed to the pathogenesis understanding of human ciliopathies. Taking the Bardet-Biedl syndrome (BBS) as an emblematic example as well as other related syndromic ciliopathies, the contribution of a wide range of models has enabled to characterize the role of the BBS proteins in the archetypical cilium but also at the level of the connecting cilium of the photoreceptors. There are more than 24 BBS genes encoding for proteins that form different complexes such as the BBSome and the chaperone proteins complex. But how they lead to retinal degeneration remains a matter of debate with the possible accumulation of proteins in the inner segment and/or accumulation of unwanted proteins in the outer segment that cannot return in the inner segment machinery. Many BBS proteins (but not the chaperonins for instance) can be modeled in primitive organisms such as
Published: 2023

4. Characterization of SSBP1-related optic atrophy and foveopathy

Author: Majida Charif, Béatrice Bocquet, Helena Huguet, Sabine Defoort-Dhellemmes, Hélène Dollfus, Vasily Smirnov, Xavier Zanlonghi, Isabelle Audo, Guy Lenaers, Isabelle Meunier, Marie Christine Picot, Carl Arndt, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Exploration de la Vision et Neuro-ophtalmologie [CHU Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Université Mohamed 1 Oujda MAROC, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), CHU Pontchaillou [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Fovea Centralis, medicine.medical_specialty, Visual acuity, genetic structures, Science, Visual impairment, Visual Acuity, Nerve fiber layer, Article, Mitochondrial Proteins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Atrophy, Ophthalmology, medicine, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, 030304 developmental biology, Genetic association study, 0303 health sciences, Retina, Multidisciplinary, business.industry, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Retinal, Hereditary eye disease, medicine.disease, Penetrance, Retinal diseases, eye diseases, Pedigree, DNA-Binding Proteins, Optic Atrophy, Cross-Sectional Studies, medicine.anatomical_structure, chemistry, Optic nerve diseases, Medicine, Female, sense organs, Age of onset, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Dominant optic atrophy (DOA) is genetically heterogeneous and most commonly caused by mutations in OPA1. To distinguish between the classical OPA1-related and the recently identified SSBP1-related DOAs, the retina and fovea of 27 patients carrying the SSBP1 p.Arg38Gln variant were scrutinized using 20° × 20° macular cube and 30° and 55° field fundus autofluorescence photographs. Age of onset, visual acuity, retinal nerve fiber layer and macular thicknesses were recorded. Three SSBP1-patients were asymptomatic, 10 had isolated DOA, and 12 had a combined DOA plus foveopathy. The foveopathy, with a tiny defect of the ellipsoid and interdigitation lines, was similar in all patients, independent of age. There were no significant statistical differences in terms of visual acuity and SD-OCT measurements between patients with isolated DOA (mean visual acuity in decimals: 0.54 ± 0.41) and those with combined foveopathy (0.50 ± 0.23). Two patients over 50 years of age developed a progressive rod-cone dystrophy, leading to severe visual impairment. SSBP1-related DOA shares similarities with OPA1-related DOA with an incomplete penetrance and an early childhood visual impairment. Nevertheless, the presence of a congenital foveopathy with no impact on visual acuity is a major criterion to distinguish SSBP1 cases and orient the appropriate genetic analysis.
Published: 2021
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5. The landscape of submicroscopic structural variants at the

Author: Bernd, Wissinger, Britta, Baumann, Elena, Buena-Atienza, Zeinab, Ravesh, Artur V, Cideciyan, Katarina, Stingl, Isabelle, Audo, Isabelle, Meunier, Beatrice, Bocquet, Elias I, Traboulsi, Alison J, Hardcastle, Jessica C, Gardner, Michel, Michaelides, Kari E, Branham, Thomas, Rosenberg, Sten, Andreasson, Hélène, Dollfus, David, Birch, Andrea L, Vincent, Loreto, Martorell, Jaume, Català Mora, Ulrich, Kellner, Klaus, Rüther, Birgit, Lorenz, Markus N, Preising, Emanuela, Manfredini, Yuri A, Zarate, Raymon, Vijzelaar, Eberhart, Zrenner, Samuel G, Jacobson, and Susanne, Kohl
Subjects: Multigene Family, Retinal Cone Photoreceptor Cells, Rod Opsins, Humans, Color Vision Defects, Gene Deletion
Abstract: Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the
Published: 2022

6. AnnotSV and knotAnnotSV: a web server for human structural variations annotations, ranking and analysis

Author: Thomas Guignard, Audrey Schalk, Jean-Baptiste Gaillard, Hélène Dollfus, Tor Solli-Nowlan, Véronique Geoffroy, Arnaud Kress, Vincent Gatinois, Sophie Scheidecker, Jean Muller, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Oslo University Hospital [Oslo], Les Hôpitaux Universitaires de Strasbourg (HUS), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, univOAK, Archive ouverte, Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Web server, AcademicSubjects/SCI00010, Interface (Java), Computational biology, Genome browser, Biology, computer.software_genre, Polymorphism, Single Nucleotide, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Ranking (information retrieval), 03 medical and health sciences, Annotation, 0302 clinical medicine, Genetics, Humans, 030304 developmental biology, Internet, 0303 health sciences, Genome, Human, Molecular Sequence Annotation, Genomics, Hyperlink, Visualization, Identification (information), Phenotype, Web Server Issue, Genomic Structural Variation, computer, Software, 030217 neurology & neurosurgery
Abstract: With the dramatic increase of pangenomic analysis, Human geneticists have generated large amount of genomic data including millions of small variants (SNV/indel) but also thousands of structural variations (SV) mainly from next-generation sequencing and array-based techniques. While the identification of the complete SV repertoire of a patient is getting possible, the interpretation of each SV remains challenging. To help identifying human pathogenic SV, we have developed a web server dedicated to their annotation and ranking (AnnotSV) as well as their visualization and interpretation (knotAnnotSV) freely available at the following address: https://www.lbgi.fr/AnnotSV/. A large amount of annotations from >20 sources is integrated in our web server including among others genes, haploinsufficiency, triplosensitivity, regulatory elements, known pathogenic or benign genomic regions, phenotypic data. An ACMG/ClinGen compliant prioritization module allows the scoring and the ranking of SV into 5 SV classes from pathogenic to benign. Finally, the visualization interface displays the annotated SV in an interactive way including popups, search fields, filtering options, advanced colouring to highlight pathogenic SV and hyperlinks to the UCSC genome browser or other public databases. This web server is designed for diagnostic and research analysis by providing important resources to the user., Graphical Abstract Graphical AbstractHere we present a web server dedicated to the annotation and ranking of structural variations (AnnotSV) as well as their visualization and interpretation (knotAnnotSV).
Published: 2021
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7. Periodontal (formerly type <scp>VIII</scp> ) <scp>Ehlers–Danlos</scp> syndrome: Description of 13 novel cases and expansion of the clinical phenotype

Author: Dan Lipsker, Marie-Cécile Manière, Jean Muller, Agathe Chammas, Aymeric Courval, Véronique Geoffroy, Elise Schaefer, Salma Adham, Salima El Chehadeh, Clarisse Billon, Sébastien Gaertner, Karelle Bénistan, Corinne Stoetzel, Agnès Bloch-Zupan, Anne-Claire Bursztejn, Anthony Reyre, Laurence Bal, Hélène Dollfus, Anne Legrand, Roland Jaussaud, Tiffany Busa, Xavier Jeunemaitre, Catherine Petit, CHU Strasbourg, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Service Obstétrique [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre national de référence des maladies vasculaires rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Rouen, Normandie Université (NU), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Sorbonne Paris Cité (USPC), Centre régional de compétence des Maladies systémiques et auto-immunes rares de l'adulte et Maladies vasculaires rares, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Charles Sadron (ICS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nanomédecine Régénérative (NanoRegMed), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Marseille, and Les Hôpitaux Universitaires de Strasbourg (HUS)
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Pathology, medicine.medical_specialty, Adolescent, 030105 genetics & heredity, Varicose Ulcer, Young Adult, 03 medical and health sciences, Aneurysm, Genetics, medicine, Tooth loss, Humans, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Aged, Periodontitis, Aortic dissection, Complement C1s, Complement C1r, business.industry, Middle Aged, medicine.disease, Hyperpigmentation, Abdominal aortic aneurysm, Dissection, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ehlers–Danlos syndrome, Child, Preschool, Mutation, Ehlers-Danlos Syndrome, Female, medicine.symptom, business, Aortic Aneurysm, Abdominal
Abstract: Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report thirteen novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.
Published: 2021
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8. Contribution of Whole-Genome Sequencing and Transcript Analysis to Decipher Retinal Diseases Associated with

Author: Anaïs F, Poncet, Olivier, Grunewald, Veronika, Vaclavik, Isabelle, Meunier, Isabelle, Drumare, Valérie, Pelletier, Béatrice, Bocquet, Margarita G, Todorova, Anne-Gaëlle, Le Moing, Aurore, Devos, Daniel F, Schorderet, Florence, Jobic, Sabine, Defoort-Dhellemmes, Hélène, Dollfus, Vasily M, Smirnov, and Claire-Marie, Dhaenens
Subjects: Neuronal Ceroid-Lipofuscinoses, Homozygote, Mutation, Retinal Dystrophies, Humans, Membrane Transport Proteins, Exons
Abstract: Biallelic gene defects in
Published: 2022

9. A<scp>BBS1SVA</scp>F retrotransposon insertion is a frequent cause of<scp>Bardet‐Biedl</scp>syndrome

Author: Corinne Stoetzel, Richard Redon, Erica E. Davis, Véronique Geoffroy, Jean-Louis Mandel, Georgios Kellaris, Samuel Nicaise, Joakim Klar, Clarisse Delvallée, Anne Sophie Leuvrey, Florence Demurger, Manuela Antin, Emmanuelle Génin, Boris Keren, Nicholas Katsanis, Niklas Dahl, Sophie Scheidecker, Elsa Nourisson, Jean Muller, Hélène Dollfus, Jean-François Deleuze, Christel Depienne, Michèle Mathieu-Dramard, Christine Poitou-Bernert, Carmen C. Leitch, Koenraad Devriendt, Sylvie Odent, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Ann & Robert H. Lurie Children's Hospital of Chicago, Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Uppsala University, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Nantes (UN), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Amiens-Picardie, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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 ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Northwestern University Feinberg School of Medicine, Agence Nationale de la Recherche, Grant/Award Number: Les Espoirs de l'Université de Strasbourg 2018, CREGEMES, Grant/Award Number: WGS 2016, Fondation pour la Recherche Médicale, Grant/Award Number: ECO20170637509, US National Institutes of Health grants, Grant/Award Numbers: DK072301, GM121317, HD042601, Chard-Hutchinson, Xavier, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Retroelements, BBS1, [SDV]Life Sciences [q-bio], Population, Medizin, 030105 genetics & heredity, Biology, Article, Cohort Studies, 03 medical and health sciences, Exon, Gene Frequency, Bardet–Biedl syndrome, Mobile element insertion, Bardet-Biedl syndrome, Genetics, medicine, Humans, Allele, SVA F, education, Genetics (clinical), Medicinsk genetik, education.field_of_study, Whole Genome Sequencing, Polydactyly, medicine.disease, Pedigree, [SDV] Life Sciences [q-bio], Mutagenesis, Insertional, Ciliopathy, founder effect, 030104 developmental biology, Female, Microtubule-Associated Proteins, Medical Genetics, Founder effect
Abstract: International audience; Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
Published: 2020
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10. <scp> WDR34 </scp> , a candidate gene for non‐syndromic rod‐cone dystrophy

Author: Wassila Carpentier, Thierry Léveillard, Christine Lonjou, Jean-Paul Saraiva, Christel Condroyer, Saddek Mohand-Said, Shomi S. Bhattacharya, Hélène Dollfus, Maria Solaguren-Beascoa, Vanessa Démontant, Lisa Emmenegger, Marie-Elise Lancelot, Elise Orhan, Kinga M. Bujakowska, Christelle Michiels, Marion Neuillé, José-Alain Sahel, Isabelle Audo, Cécile Méjécase, Eric A. Pierce, Mélanie Letexier, Christina Zeitz, Aline Antonio, Ministère de l’Enseignement supérieur et de la Recherche (France), Fondation de France, Foundation Fighting Blindness, Fondation Voir et Entendre, Agence Nationale de la Recherche (France), National Eye Institute (US), Région Ile-de-France, and Association Française contre les Myopathies
Subjects: Adult, Male, 0301 basic medicine, Candidate gene, WD40 Repeats, genetic structures, WDR34, Whole-exomesequencing, 030105 genetics & heredity, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Retinitis pigmentosa, Genetics, Rod-cone dystrophy, medicine, Humans, Genetic Association Studies, Genetics (clinical), Exome sequencing, Non-syndromic rod-cone dystrophy, Mutation, Dystrophy, Disease gene identification, medicine.disease, Pedigree, KIAA2026, Ciliopathy, 030104 developmental biology, sense organs, Carrier Proteins, Cone-Rod Dystrophies
Abstract: Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD., Doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche; Europe exchange 2018 Erasmus; European Reintegration Grant, Grant/Award Number: PERG04-GA-2008-231125; Fondation de France-Berthe Fouassier; Foundation Fighting Blindness, Grant/Award Number: Grant # CD-CL-0808-0466-CHNO CIC503 recogn; Foundation Voir et Entendre; French Agence Nationale de la Recherche, Grant/Award Numbers: IHU FOReSIGHT: ANR-18-IAHU-0001, LIFESENSES: ANR-10-LABX-65; National Eye Institute [R01EY012910 (EAP), R01EY026904 (KMB/EAP) and P30EY014104 (MEEI core support)], the Foundation Fighting
Published: 2020
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11. In Vitro Fertilization assisted by IntraCytoplasmic Sperm Injection in a male patient with Bardet-Biedl syndrome

Author: Cécile Grèze, Jean Muller, Larissa Schindler, Sylvie Rossignol, Nadia Messaddeq, Anna Zinetti‐Bertschy, Nathalie Goetz, Hélène Dollfus, and Isabelle Koscinski
Subjects: Male, Genetics, Humans, Fertilization in Vitro, Sperm Injections, Intracytoplasmic, Bardet-Biedl Syndrome, Spermatozoa, Genetics (clinical)
Published: 2022

12. Cystoid maculopathy is a frequent feature of Cohen syndrome-associated retinopathy

Author: Eléonore Lizé, Grazia M.S. Mancini, Christel Thauvin-Robinet, Vincent Lhussiez, Hélène Dollfus, Saddek Mohand-Said, Niyazi Acar, Xavier Zanlonghi, José-Alain Sahel, Pierre-Henry Gabrielle, Isabelle Audo, Emeline F. Nandrot, Laurence Duplomb, Catherine Creuzot-Garcher, Alberta A H J Thiadens, Yaumara Perdomo, Muhammad Ansar, Romain Da Costa, Christina Zeitz, Laurence Faivre, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), DHU Sight Restore [Paris], CHU Pontchaillou [Rennes], Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Institute of Molecular and Clinical Ophthalmology Basel [Basel, Switzerland] (IMCOB), Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], Centre de Référence Déficiences Intellectuelles de Causes Rares [CHU Dijon] (CRDICR), Service d'Ophtalmologie (CHU de Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institute of Molecular and Clinical Ophthalmology Basel, CH-4031 Basel, Switzerland, Jules Gonin Eye Hospital, Université de Lausanne = University of Lausanne (UNIL), Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), the Conseil Régional de Bourgogne and the European Union through the Plan d'Actions Régional pour l'Innovation (PARI) and the PO FEDER-FSE Bourgogne 2014/2020 programs. This work is also supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with COH1 Research Alliance (L.F., R.D.C., C.T., L.D.), and with funds from the JED Fondation (L.F.) as well as from Ville de Paris and Region Ile de France, LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program [ANR-11-IDEX-0004–0], IHU FOReSIGHT [ANR-18-IAHU-0001] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program and Foundation Fighting Blindness center grant [C-CMM-0907–0428-INSERM04]., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Julien, Sabine, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Ophthalmology, Clinical Genetics, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Lausanne (UNIL)
Subjects: Male, genetic structures, Developmental Disabilities, Macular Degeneration, 0302 clinical medicine, Myopia, Medicine, Young adult, Child, 0303 health sciences, Multidisciplinary, Retinal Degeneration, Medical genetics, Retinal diseases, 3. Good health, VPS13B, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Preschool, Cohort, Microcephaly, Muscle Hypotonia, Female, Tomography, Optical Coherence, Retinopathy, Adult, medicine.medical_specialty, Adolescent, Science, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Macular Edema, Article, Retina, Fingers, Young Adult, 03 medical and health sciences, Intellectual Disability, Ophthalmology, Humans, Obesity, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, 030304 developmental biology, Cohen syndrome, business.industry, Dystrophy, Hereditary eye disease, medicine.disease, eye diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, Maculopathy, sense organs, business
Abstract: Cohen syndrome (CS) is a rare syndromic form of rod-cone dystrophy. Recent case reports have suggested that cystoid maculopathy (CM) could affect CS patients with an early onset and high prevalence. Our study aims at improving our understanding and management of CM in CS patients through a retrospective case series of ten CS patients with identified pathogenic variants in VPS13B. Longitudinal optical coherence tomography (OCT) imaging was performed and treatment with carbonic anhydrase inhibitors (CAI) was provided to reduce the volume of cystoid spaces. CM affected eight out of ten patients in our cohort. The youngest patient showed a strong progression of macular cysts from the age of 4.5 to 5 years despite oral CAI medication. Other teenage and young adult patients showed stable macular cysts with and without treatment. One patient showed a moderate decrease of cystoid spaces in the absence of treatment at 22 years of age. Through a correlative analysis we found that the volume of cystoid spaces was positively correlated to the thickness of peripheral and macular photoreceptor-related layers. This study suggests that CAI treatments may not suffice to improve CM in CS patients, and that CM may resolve spontaneously during adulthood as photoreceptor dystrophy progresses.
Published: 2021
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13. Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Author: Kirsley Chennen, Philippe Loget, Alix Clemenson, Elise Schaefer, Marie-Josée Perez, Elsa Nourisson, Laura Mary, Corinne Stoetzel, Bernard Gasser, Jean Muller, Annie Buenerd, Lucile Pinson, Louise Devisme, Florence Petit, Olivier Poch, Anne Sophie Leuvrey, Fabien Guimiot, Patrice Bouvagnet, Caroline Rooryck-Thambo, Brigitte Leroy, Manuela Antin, Tania Attié-Bitach, Jelena Martinovic, Fanny Pelluard, Raymonde Bouvier, Hélène Dollfus, Brigitte Gilbert-Dussardier, Elisabeth Alanio-Detton, Maria Cristina Antal, and Philippe Khau Van Kien
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Genotype, Biopsy, Autopsy, Disease, 030105 genetics & heredity, 03 medical and health sciences, Bardet–Biedl syndrome, Prenatal Diagnosis, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bardet-Biedl Syndrome, Alleles, Genetic Association Studies, Genetics (clinical), Cystic kidney, Fetus, Polydactyly, business.industry, medicine.disease, Ciliopathy, Phenotype, 030104 developmental biology, Amino Acid Substitution, Mutation, business
Abstract: Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.
Published: 2019
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14. Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study

Author: Claire Forde, Emma Burkitt-Wright, Peter D. Turnpenny, Eric Haan, John Ealing, Sahar Mansour, Muriel Holder, Nayana Lahiri, Abhijit Dixit, Annie Procter, Laurence Pacot, Dominique Vidaud, Yline Capri, Marion Gerard, Hélène Dollfus, Elise Schaefer, Chloé Quelin, Sabine Sigaudy, Tiffany Busa, Gabriella Vera, Lena Damaj, Ludwine Messiaen, David A. Stevenson, Peter Davies, Sheila Palmer-Smith, Alison Callaway, Pierre Wolkenstein, Eric Pasmant, and Meena Upadhyaya
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Neurofibroma, Neurofibromatosis 1, Cafe-au-Lait Spots, Genetics, Humans, Longitudinal Studies, Genetics (clinical), Genetic Association Studies
Abstract: Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual—a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with ‘classical’, clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype–phenotype association is fundamental to accurate prognostication for families and caregivers.
Published: 2021

15. Improved performance and safety from Argus II retinal prosthesis post-approval study in France

Author: Pierre-Olivier Barale, Jessy D. Dorn, Saddek Mohand-Said, Sarah Ayello-Scheer, Fouzia Rezaigua-Studer, Jean-François Korobelnik, José-Alain Sahel, David Gaucher, Marie-Noëlle Delyfer, and Hélène Dollfus
Subjects: Male, medicine.medical_specialty, Activities of daily living, Time Factors, genetic structures, Retinal implant, Visual Acuity, Prosthesis Design, Retina, Prosthesis Implantation, 03 medical and health sciences, 0302 clinical medicine, Endophthalmitis, Device Approval, Medicine, Humans, Prospective Studies, Adverse effect, computer.programming_language, Argus, business.industry, Incidence, General Medicine, Middle Aged, medicine.disease, Visual Prosthesis, Ophthalmology, Improved performance, Retinal Prosthesis, Cohort, 030221 ophthalmology & optometry, Physical therapy, Female, France, business, computer, 030217 neurology & neurosurgery, Retinitis Pigmentosa, Follow-Up Studies
Abstract: PURPOSE: To evaluate the post-approval long-term outcomes of the Argus II Retinal Prosthesis, with a specific focus on its functional visual benefit in patients' daily activities. METHODS: Eighteen patients with bare light perception due to end-stage retinitis pigmentosa were included in a French prospective, multicentre, single-arm study and followed for 2 years. Visual benefit in patients' daily activities was monitored through the use of the Functional Low-vision Observer Rated Assessment (FLORA), and the final score at 2 years was the primary effectiveness outcome. Standardized visual assessments were also performed. Device- or procedure-related adverse events were recorded. RESULTS: Seventeen subjects completed the study. Positive impacts of the Argus II system on functional vision and well-being were demonstrated for over 70% of subjects on the FLORA. Among the daily activities/tasks tested, finding doorways was one of the most statistically significantly improved tasks (p
Published: 2020

16. Consensus clinical management guidelines for Alström syndrome

Author: Shyam Madathil, Hélène Dollfus, Vincent Marion, Timothy Barrett, Ann Chivers, Marina Valenti, Richard P. Steeds, Clair A. Francomano, Natascia Tahani, Matthew J. Armstrong, Meral Gunay-Aygun, Charlotte Dawson, Selma Düzenli, Pietro Maffei, Gabriella Milan, Kerry Leeson-Beevers, Francesca Favaretto, Tarekegn Geberhiwot, Joan C. Han, Adrian T. Warfield, Francesca Dassie, Diana Valverde, Richard B Paisey, BAİBÜ, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and Düzenli, Selma
Subjects: Pediatrics, medicine.medical_specialty, Consensus, Cardiomyopathy, 2415 Biología Molecular, lcsh:Medicine, Disease, Guidelines, Deafness, Blindness, Childhood obesity, Quality of life (healthcare), Rare Disease, Non-alcoholic Fatty Liver Disease, medicine, Humans, Pharmacology (medical), Obesity, Alstrom syndrome, Child, Position Statement, Genetics (clinical), Alstrom Syndrome, business.industry, 2409 Genética, lcsh:R, fungi, Genetic disorder, Alström syndrome, Insulin resistance, Non-alcoholic fatty liver disease, Rare disease, General Medicine, Evidence-based medicine, medicine.disease, Practice Guidelines as Topic, Quality of Life, Age of onset, Insulin Resistance, business
Abstract: Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.
Published: 2020

17. High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3

Author: Sophie Scheidecker, Hugues Flodrops, Jean-Luc Alessandri, Corinne Stoetzel, Aurélie Gouronc, Hélène Dollfus, Manuela Antin, Paul Gueguen, Marie-Line Jacquemont, Bérénice Doray, Françoise Darcel, Frédérique Payet, Hanitra Randrianaivo, Vincent Zilliox, Jean Muller, Elsa Nourisson, and Anne-Sophie Leuvrey
Subjects: 0301 basic medicine, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Genetic counseling, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Bardet–Biedl syndrome, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Genotyping, Bardet-Biedl Syndrome, Genetics (clinical), Alleles, Polydactyly, ADP-Ribosylation Factors, Haplotype, medicine.disease, Founder Effect, Pedigree, Ciliopathy, 030104 developmental biology, Haplotypes, Child, Preschool, Mutation, Female, Founder effect, SNP array
Abstract: Bardet-Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Reunion Island using sequencing (Sanger and high-throughput methods) and SNP array. In eight families (12 individuals) we identified the same ARL6/BBS3 variation [c.535G > A, p.(Asp179Asn)]. Bioinformatics and functional analyses revealed an effect of this variant on the splicing of ARL6/BBS3. Owing to the relatively high frequency of this variant, a possible founder effect was suspected. Genotyping of six individuals revealed a common 3.8-Mb haplotype and estimated the most recent common ancestor to about eight generations confirmed by the known genealogy. Knowledge of this founder effect modifies our diagnostic strategy and enables a personalized genetic counseling for patients from La Reunion Island. Being the first description of BBS patients from La Reunion Island, we could estimate its prevalence between ~1/45000 and ~ 1/66000 individuals.
Published: 2020

18. A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum

Author: Anne-Sophie Guilbert, Charlie De Melo, Elise Schaefer, Benjamin Durand, Hélène Dollfus, Corinne Stoetzel, Nadège Calmels, Leonardo Donato, Dana Timbolschi, Nadine Kempf, Sophie Scheidecker, Dominique Astruc, Arnaud Sauer, Maria Cristina Antal, Salima El Chehadeh, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Heart Defects, Congenital, Pathology, medicine.medical_specialty, Developmental Disabilities, Glaucoma, 030105 genetics & heredity, Osteochondrodysplasias, Craniofacial Abnormalities, 03 medical and health sciences, Camptodactyly, Megalocornea, Frank–ter Haar syndrome, Genetics, Medicine, Humans, Abnormalities, Multiple, Craniofacial, Genetics (clinical), Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Infant, Newborn, Infant, General Medicine, medicine.disease, Hypotonia, Buphthalmos, 030104 developmental biology, Phenotype, Invadopodia, Female, medicine.symptom, business
Abstract: Frank-ter Haar syndrome (FTHS) is a rare autosomal recessive syndrome resulting from mutations in the SH3PXD2B gene involved in the formation of podosomes and invadopodia which have a role in extracellular matrix remodelling and cell migration. FTHS is characterized by facial dysmorphism, megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies. To date, 40 patients have been reported in the literature with a clinical diagnosis of FTHS, only 20 patients having identified mutations. We present a review of these 20 reported patients and describe a patient born to non-consanguineous parents, with intrauterine growth retardation, hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect, thin corpus callosum and craniofacial features suggestive of FTHS. Clinical evolution resulted in buphthalmos worsening, coarsening of the facial features and respiratory failure leading to death at 4,5 months. Diagnosis was confirmed by the identification of a previously known homozygous mutation c.969delG, p.(Arg324Glyfs*19) in SH3PXD2B. This is the first description of very severe phenotype with lethal respiratory impairment in FTHS. Since very few patients are described in the literature, and 2 out of the 3 patients carrying the c.969delG mutation had a favourable clinical course, more cases are needed to better characterize the phenotype and understand the natural history of this syndrome. Furthermore, we hypothesize that the alteration of podosomes function could lead to a reduction of the extracellular matrix degradation and accumulation of the latter in the extracellular space, which might explain the coarsening of the facial features and the severe refractory glaucoma.
Published: 2020
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19. Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene

Author: Jean-François Korobelnik, Xavier Zanlonghi, Dominique Bonneau, Benoit Arveiler, Caroline Rooryck-Thambo, Perrine Pennamen, Yaurama Perdomo, Vincent Michaud, Sabine Defoort-Dhellemmes, C. Paya, Hélène Dollfus, Fanny Morice-Picard, Christian P. Hamel, Claudio Plaisant, Solene Monfermé, Catherine Duncombe-Poulet, Eulalie Lasseaux, Isabelle Drumare, CHU Bordeaux [Bordeaux], Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Visual acuity, Photophobia, albinism, Compound heterozygosity, 0302 clinical medicine, Child, A/p.Arg402Gln), Aged, 80 and over, Monophenol Monooxygenase, Middle Aged, Oculocutaneous albinism, Sensory Systems, Hypoplasia, Pedigree, Phenotype, Albinism, Oculocutaneous, Child, Preschool, Brown hair, visual_art, Albinism, foveal hypoplasia, Female, medicine.symptom, hypopigmentation, nystagmus, Adult, medicine.medical_specialty, Adolescent, R402Q (c.1205G&gt, genotype-phenotype correlation, TYR gene, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, visual_art.color, Ophthalmology, medicine, Humans, Aged, Retrospective Studies, Hypopigmentation, business.industry, Infant, Newborn, Infant, medicine.disease, 030104 developmental biology, Mutation, 030221 ophthalmology & optometry, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: AimOculocutaneous albinism type 1 (OCA1) is due to TYR mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the TYR gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant.MethodsIn our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of TYR, and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the ‘R402Q-OCA1’ group. 146 patients harboured two pathogenic variants of the TYR gene other than R402Q. Clinical records were available for 119 of them, constituting the ‘Classical-OCA1’ group.ResultsMost R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38±0.21 logarithm of the minimum angle of resolution vs 0.76±0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of TYR in cis with R402Q, suggested by others, showed no significant impact on the phenotype.ConclusionThe R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis.
Published: 2018
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20. Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing

Author: Iris, Barny, Isabelle, Perrault, Marlène, Rio, Hélène, Dollfus, Sabine, Defoort-Dhellemmes, Josseline, Kaplan, Jean-Michel, Rozet, and Xavier, Gerard
Subjects: Cytoskeletal Proteins, Retinal Diseases, Antigens, Neoplasm, Codon, Nonsense, RNA Splicing, Siblings, Mutation, Humans, Cell Cycle Proteins, Exons
Abstract: CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.
Published: 2019

21. Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease

Author: Josseline Kaplan, Tania Attié-Bitach, Christian P. Hamel, Christel Michel, Isabelle Perrault, Xavier Gérard, Sophie Thomas, Hélène Dollfus, Nicolas Goudin, Mickael Soussan, Iris Barny, Marlène Rio, Jean-Michel Rozet, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-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 Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and Centre National de la Recherche Scientifique (CNRS)-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 Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, 0301 basic medicine, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Nonsense mutation, Mutant, Cell Cycle Proteins, Biology, Compound heterozygosity, medicine.disease_cause, Autoantigens, 03 medical and health sciences, Exon, 0302 clinical medicine, Retinal Diseases, Antigens, Neoplasm, Genetics, medicine, Humans, Cilia, Child, Eye Proteins, Molecular Biology, Genetics (clinical), Centrosome, Mutation, Tumor Suppressor Proteins, Cilium, Exons, General Medicine, Fibroblasts, Molecular biology, Exon skipping, Neoplasm Proteins, Cytoskeletal Proteins, Protein Transport, 030104 developmental biology, Codon, Nonsense, RNA splicing, Codon, Terminator, Female, 030217 neurology & neurosurgery
Abstract: International audience; CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base-pair deletion in exon 17, introducing a premature termination codon (PTC) in exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in exon 8 (c.508A\textgreaterT, p.Lys170*) and exon 32 (c.4090G\textgreaterT, p.Glu1364*), respectively. Some CEP290 lacking exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing (NAS) alone (exon 8), or with BES (exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.
Published: 2018
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22. Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome

Author: Cathy Obringer, Audrey Schalk, Nadège Calmels, Jamel Chelly, Géraldine Greff, Hélène Dollfus, Nathalie Drouot, and Vincent Laugel
Subjects: Male, 0301 basic medicine, Microcephaly, Biology, medicine.disease_cause, Article, Cockayne syndrome, 03 medical and health sciences, Exon, Genetics, medicine, Humans, Child, Cockayne Syndrome, Cells, Cultured, Genetics (clinical), Mutation, Infant, Splicing regulatory element, medicine.disease, Introns, DNA Repair Enzymes, 030104 developmental biology, ERCC8, RNA Splice Sites, ERCC6, Transcription Factors, Minigene
Abstract: Cockayne syndrome is an autosomal recessive multisystem disorder characterized by intellectual disability, microcephaly, severe growth failure, sensory impairment, peripheral neuropathy, and cutaneous sensitivity. This rare disease is linked to disease-causing variations in the ERCC6 (CSB) and ERCC8 (CSA) genes. Various degrees of severity have been described according to age at onset and survival, without any clear genotype-phenotype correlation. All types of nucleotide changes have been observed in CS genes, including splice variations mainly affecting the splice site consensus sequences. We report here the case of two brothers from a consanguineous family presenting a severe but long-term survival phenotype of Cockayne syndrome. We identified in the patients a homozygous deep intronic nucleotide variation causing the insertion of a cryptic exon in the ERCC8 (CSA) transcript, by modifying intronic regulatory elements important for exon definition. The pathogenesis of the nucleotide variant NG_009289.1(NM_000082.3):c.173+1119G>C was validated in vitro with a reporter minigene system. To our knowledge, these are the first Cockayne patients described with this kind of disease-causing variation, though molecular mechanism underlying early onset symptoms and unexpected slow raise of progression of the disease remain to be elucidated.
Published: 2018
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23. AnnotSV: an integrated tool for structural variations annotation

Author: Jean Muller, Amélie Piton, Yvan Herenger, Hélène Dollfus, Véronique Geoffroy, Corinne Stoetzel, Arnaud Kress, Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], 0301 basic medicine, Statistics and Probability, Source code, Computer science, media_common.quotation_subject, Genomics, Computational biology, Biochemistry, Genome, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, Annotation, 0302 clinical medicine, Gene Frequency, Humans, Nucleotide, 1000 Genomes Project, Indel, Molecular Biology, Allele frequency, media_common, chemistry.chemical_classification, Genome, Human, Molecular Sequence Annotation, Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, chemistry, Genomic information, Human genome, Software, 030217 neurology & neurosurgery
Abstract: Summary Structural Variations (SV) are a major source of variability in the human genome that shaped its actual structure during evolution. Moreover, many human diseases are caused by SV, highlighting the need to accurately detect those genomic events but also to annotate them and assist their biological interpretation. Therefore, we developed AnnotSV that compiles functionally, regulatory and clinically relevant information and aims at providing annotations useful to (i) interpret SV potential pathogenicity and (ii) filter out SV potential false positive. In particular, AnnotSV reports heterozygous and homozygous counts of single nucleotide variations (SNVs) and small insertions/deletions called within each SV for the analyzed patients, this genomic information being extremely useful to support or question the existence of an SV. We also report the computed allelic frequency relative to overlapping variants from DGV (MacDonald et al., 2014), that is especially powerful to filter out common SV. To delineate the strength of AnnotSV, we annotated the 4751 SV from one sample of the 1000 Genomes Project, integrating the sample information of four million of SNV/indel, in less than 60 s. Availability and implementation AnnotSV is implemented in Tcl and runs in command line on all platforms. The source code is available under the GNU GPL license. Source code, README and Supplementary data are available at http://lbgi.fr/AnnotSV/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2018
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24. Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

Author: Fouzia Studer, Corinne Stoetzel, Jean Muller, Amélie Piton, Aline Schneider, Olivier Poch, Christelle Etard, Damien Plassard, Clarisse Delvallée, Sabine Sigaudy, Hélène Dollfus, Alejandro Estrada-Cuzcano, Uwe Strähle, Elise Schaefer, Francesca Mattioli, Sophie Scheidecker, Kirsley Chennen, Véronique Geoffroy, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Fluorescent Antibody Technique, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ciliopathies, Pronephric duct, Sciences du Vivant [q-bio]/Génétique, Fingers, Consanguinity, 03 medical and health sciences, Exome Sequencing, Sciences du Vivant [q-bio]/Biologie cellulaire, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Zebrafish, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polydactyly, biology, Gene Expression Profiling, Cilium, Homozygote, 030305 genetics & heredity, Haplotype, Intracellular Signaling Peptides and Proteins, Genetic Variation, Membrane Proteins, Toes, medicine.disease, biology.organism_classification, Immunohistochemistry, Phenotype, Pedigree, 3. Good health, Transcriptome, Signal Transduction
Abstract: Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.
Published: 2019
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25. Correction to: An ontological foundation for ocular phenotypes and rare eye diseases

Author: Panagiotis I. Sergouniotis, Emmanuel Maxime, Dorothée Leroux, Annie Olry, Rachel Thompson, Ana Rath, Peter N. Robinson, Hélène Dollfus, and for the ERN-EYE Ontology Study Group
Subjects: 0301 basic medicine, Eye Diseases, genetic structures, education, Pharmacology toxicology, lcsh:Medicine, 030105 genetics & heredity, behavioral disciplines and activities, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Humans, Pharmacology (medical), Precision Medicine, Workgroup, Genetics (clinical), Evidence-Based Medicine, lcsh:R, Correction, Computational Biology, Foundation (evidence), General Medicine, eye diseases, humanities, Biological Ontologies, Ontology, Optometry, Psychology, 030217 neurology & neurosurgery
Abstract: The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related component of two well-established biomedical ontologies, the Human Phenotype Ontology (HPO; includes signs, symptoms and investigation findings) and the Orphanet Rare Disease Ontology (ORDO; includes rare disease nomenclature/nosology).A variety of approaches were used including automated matching to existing resources and extensive manual curation. To achieve the latter, a study group including clinicians, patient representatives and ontology developers from 17 countries was formed. A broad range of terms was discussed and validated during a dedicated workshop attended by 60 members of the group.A comprehensive, structured and well-defined set of terms has been agreed on including 1106 terms relating to ocular phenotypes (HPO) and 1202 terms relating to rare eye disease nomenclature (ORDO). These terms and their relevant annotations can be accessed in http://www.human-phenotype-ontology.org/ and http://www.orpha.net/ ; comments, corrections, suggestions and requests for new terms can be made through these websites. This is an ongoing, community-driven endeavour and both HPO and ORDO are regularly updated.To our knowledge, this is the first effort of such scale to provide terminology standards for the rare eye disease community. We hope that this work will not only improve coding and standardise information exchange in clinical care and research, but also it will catalyse the transition to an evidence-based precision ophthalmology paradigm.
Published: 2019
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26. One

Author: Laurence, Pacot, Cyril, Burin des Roziers, Ingrid, Laurendeau, Audrey, Briand-Suleau, Audrey, Coustier, Théodora, Mayard, Camille, Tlemsani, Laurence, Faivre, Quentin, Thomas, Diana, Rodriguez, Sophie, Blesson, Hélène, Dollfus, Yvon-Gauthier, Muller, Béatrice, Parfait, Michel, Vidaud, Brigitte, Gilbert-Dussardier, Catherine, Yardin, Benjamin, Dauriat, Christian, Derancourt, Dominique, Vidaud, and Eric, Pasmant
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, SPRED1, Neurofibromatosis 1, Neurofibromin 1, Adolescent, Cafe-au-Lait Spots, neurofibromatosis type 1, eye diseases, Article, nervous system diseases, Pedigree, Legius syndrome, Phenotype, NF1, Mutation, Humans, Female, de novo variant, Child, neoplasms, Adaptor Proteins, Signal Transducing
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.
Published: 2019

27. Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources

Author: Kayli Rageth, Cynthia L. Smith, Renske Oegema, Julius O.B. Jacobsen, Xingmin Aaron Zhang, Kathleen E. Sullivan, James P. Balhoff, Ayushi Hegde, David Osumi-Sutherland, Gareth Baynam, Rachel Thompson, Matthew T. Wheeler, Cornelius F. Boerkoel, Hélène Dollfus, Nomi L. Harris, Daniel Durkin, Dorothée Leroux, Joshua D. Milner, Melissa A. Haendel, Annie Olry, Dylan Gratian, Nicolas Matentzoglu, Anna Jansen, David Gómez-Andrés, Zafer Yüksel, Hugh Dawkins, Peter N. Robinson, Ruth C. Lovering, Luigi D. Notarangelo, Michael M. Segal, Maria G. Della Rocca, Sergio Rosenzweig, Julie A. McMurry, Catherine Hajek, Francisco Castellanos, Valentina Cipriani, Willie H. Chang, Sergi Beltran, Ahmed Muaz, Leigh C. Carmody, Marc Hanauer, Jenna R.E. Bergerson, Hanns Lochmüller, Halima Lourghi, Tom Conlin, Charlotte Cunningham-Rundles, James R. Priest, Richard Palmer, Shruti Marwaha, Panagiotis I. Sergouniotis, Amy D. Klion, Alexandra F. Freeman, Morgan Similuk, Michael Brudno, Melody C. Carter, Stanley J. F. Laulederkind, Michael A. Gargano, Susan M. Bello, Tudor Groza, Christopher J. Mungall, Damian Smedley, Hannah Blau, Daniel Danis, Jean-Philippe F. Gourdine, Sebastian Köhler, Murat Sincan, Ana Rath, Nicole Vasilevsky, Andrea L. Storm, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, and Pediatrics
Subjects: Vocabulary, media_common.quotation_subject, Knowledge Bases, Interoperability, Biology, Ontology (information science), Congenital Abnormalities, World Wide Web, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Information and Computing Sciences, Human Phenotype Ontology, Databases, Genetic, Genetics, Database Issue, Humans, Genetic Predisposition to Disease, 030304 developmental biology, media_common, 0303 health sciences, Internet, Whole Genome Sequencing, business.industry, Computational Biology, Genetic Variation, Biological Ontologies, Biological Sciences, 3. Good health, Phenotype, Knowledge base, The Internet, business, Environmental Sciences, 030217 neurology & neurosurgery, Developmental Biology, De facto standard
Abstract: National Institutes of Health (NIH), Monarch Initiative [OD #5R24OD011883]; Forums for Integrative Phenomics [U13 CA221044-01]; NCATS Data Translator [1OT3TR002019]; NCATS National Center for Digital Health Informatics Innovation [U24 TR002306];NIH Data Commons [1 OT3 OD02464-01 UNCCH]; Cost Action CA 16118 Neuro-MIG; British Heart Foundation Programme Grant [RG/13/5/30112]; Division of Intramural Research; NIAID; NIH; E-RARE project Hipbi-RD [01GM1608]; European Union's Horizon 2020 Research and Innovation Programme [779257]. Funding for open access charge: NIH; Donald A. Roux Family Fund (to P.N.R.). The Human Phenotype Ontology (HPO) - a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases - is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.
Published: 2019
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28. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Author: Chris Balak, Hélène Dollfus, Sumaiya Iqbal, Newell Belnap, Kristin G. Monaghan, Lorida Llaci, Sampathkumar Rangasamy, Véronique Geoffroy, Jean-Louis Mandel, Dennis Lal, Jamel Chelly, Keri Ramsey, Maïté Courel, Kirsty McWalter, Ignazio S. Piras, Marcus Naymik, Rolph Pfundt, Michèle Ernoult-Lange, Wayne M. Jepsen, Vinodh Narayanan, Antony Le Béchec, Dominique Weil, Kristine K. Bachman, Ryan Richholt, Szabolcs Szelinger, Matthew J. Huentelman, Johanna ter Beest, Arthur Campbell, Ingrid M. Wentzensen, Francesca Mattioli, Marianne Bénard, Jean Muller, Jean-François Deleuze, Amélie Piton, Anne Boland, Elise Schaefer, Patrick Rump, Matt De Both, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], GeneDx [Gaithersburg, MD, USA], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Les Hôpitaux Universitaires de Strasbourg (HUS), Cologne Center for Genomics, University of Cologne, Laboratoire de Biologie du Développement [IBPS] (LBD), weil, dominique, The Translational Genomics Research Institute (TGen), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Groningen [Groningen], Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CEA- Saclay (CEA), Lerner Research Institute [Cleveland, OH, USA], Cleveland Clinic, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CDF (laboratoire)), Collège de France (CdF (institution)), and Bénard, Marianne
Subjects: [SDV]Life Sciences [q-bio], RecA domain, DENDRITES, DEAD-box RNA Helicases, 0302 clinical medicine, Missense mutation, NEURONS, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, DEAD-box, RNA Helicase A, [SDV] Life Sciences [q-bio], helicase, intellectual disability, missense variants, DDX3X, COMMON-CAUSE, mRNA metabolism, RNA helicase, processing bodies, DEAD box, PROTEINS, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, METABOLISM, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Proto-Oncogene Proteins, DDX6, TRANSLATIONAL REPRESSION, REVEALS, Humans, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, MUTATIONS, Helicase, RNA, DExD/H-box, FRAMEWORK, neurodevelopmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, p-bodies, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
Published: 2019
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29. Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy

Author: Béatrice Lannes, Stéphane Kremer, Jean Muller, Bruno Rinaldi, Séverine Bär, Valérie Pelletier, Hubert Dominique Becker, Véronique Geoffroy, Frédéric Fischer, Christine Tranchant, Cécile Acquaviva-Bourdain, Sylvie Friant, Hélène Dollfus, Cécile Pagan, Sophie Scheidecker, Marc Mirande, Corinne Stoetzel, Les Hôpitaux Universitaires de Strasbourg (HUS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie [CHU Strasbourg], CHU Strasbourg, Centre de référence pour les affections ophtalmologiques héréditaires (CARGO), Hôpitaux Universitaires de Strasbourg, Hospices Civils de Lyon (HCL), Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal [CHU Lyon] (Centre de Biologie et Pathologie Est), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est, Hôpital de Hautepierre [Strasbourg], 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), Département Biologie des Génomes (DBG), 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), Assemblages supramoléculaires et traduction (MARS), 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), Service de Neurologie [Strasbourg], and CHU Strasbourg-Hopital Civil
Subjects: Gene isoform, Lysine-tRNA Ligase, Models, Molecular, mitochondrial respiratory chain defect, Protein Conformation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, translation, lysyl-tRNA synthetase, Neurological disorder, Biology, Mitochondrion, p38 Mitogen-Activated Protein Kinases, Sciences du Vivant [q-bio]/Génétique, Optic neuropathy, Amino Acyl-tRNA Synthetases, Electron Transport Complex IV, 03 medical and health sciences, deafness, aaRS, Optic Nerve Diseases, Genetics, medicine, Humans, Genetic Predisposition to Disease, Nonsyndromic deafness, Amino Acid Sequence, neurological disorder, Gene, Genetics (clinical), Alleles, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Electron Transport Complex I, 030305 genetics & heredity, Respiratory chain complex, Translation (biology), Fibroblasts, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Pedigree, optic neuropathy, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Mutation, Sensation Disorders, Nervous System Diseases, Protein Binding
Abstract: Mutations in genes encoding aminoacyl‐tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl‐tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl‐tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole‐exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild‐type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear‐encoded lysine‐rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.
Published: 2019
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30. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Author: Maria, Kousi, Onuralp, Söylemez, Aysegül, Ozanturk, Niki, Mourtzi, Sebastian, Akle, Irwin, Jungreis, Jean, Muller, Christopher A, Cassa, Harrison, Brand, Jill Anne, Mokry, Maxim Y, Wolf, Azita, Sadeghpour, Kelsey, McFadden, Richard A, Lewis, Michael E, Talkowski, Hélène, Dollfus, Manolis, Kellis, Erica E, Davis, Shamil R, Sunyaev, and Nicholas, Katsanis
Subjects: Cohort Studies, Genetic Variation, Humans, Exome, Bardet-Biedl Syndrome, Alleles
Abstract: The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet-Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes-a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model for secondary-variant burden analysis in recessive disorders.
Published: 2018

31. Long term follow up of two independent patients with Schinzel–Giedion carrying SETBP1 mutations

Author: Sophie Scheidecker, Valérie Pelletier, Michel Fischbach, Anne de Saint Martin, Elise Schaefer, Jean-Michel Clavert, Yvan Herenger, Joelle Terzic, Yves Alembik, Hélène Dollfus, Marie-Cécile Manière, Corinne Stoetzel, and Dominique Christmann
Subjects: Male, Hypertrichosis, Pediatrics, medicine.medical_specialty, Adolescent, Long term follow up, Molecular Sequence Data, Nails, Malformed, Disease, Nephrolithiasis, Craniofacial Abnormalities, Intellectual Disability, Intellectual disability, Temporal bone, Genetics, medicine, Humans, Abnormalities, Multiple, Amino Acid Sequence, Child, Genetics (clinical), business.industry, Genitourinary system, Schinzel–Giedion syndrome, Brain, Nuclear Proteins, General Medicine, Prognosis, medicine.disease, Magnetic Resonance Imaging, Pedigree, Face, Microcephaly, Female, Megacalycosis, Psychomotor Disorders, Carrier Proteins, business, Hand Deformities, Congenital, Follow-Up Studies
Abstract: Schinzel–Giedion syndrome (SGS, MIM #269150) is a rare syndrome characterized by severe intellectual disability, typical facial gestalt, hypertrichosis and multiple congenital malformations including skeletal, genitourinary, renal and cardiac abnormalities. The prognosis of SGS is very severe and death occurs generally within a few years after birth. In 2002, we reported 2 children with SGS with a follow-up of 3 years. They presented a very similar and particular phenotype associating distinctive facial gestalt, severe developmental delay, megacalycosis, progressive neurodegeneration, alacrimi, corneal hypoesthesia and deafness. Furthermore, temporal bone imaging revealed a tuning-fork malformation of the stapes. In 2010, Hoischen et al. identified in SGS patients pathogenic heterozygous de novo mutations in SETBP1. We sequenced SETBP1 in our patients and found the previously reported c.2608G>A (p.Gly870Ser) mutation in both children. Since 2002, one of our patients died at 6 years old and the other patient is still alive at 15 years old. Such a life expectancy has never been reported so far. We describe herein the follow up of the 2 children during 6 and 15 years respectively. This article gives further evidence of the implication of SETBP1 as the major gene of SGS, and reports the previously unseen natural evolution of the disease in a 15 years old patient.
Published: 2015
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32. Alström Syndrome: Mutation Spectrum ofALMS1

Author: Francesca Favaretto, Roberto Vettor, Gabriella Milan, Darrell L. Dinwiddie, Gayle B. Collin, Emily G. Farrow, Hélène Dollfus, Jean Muller, Juergen K Naggert, Stephen F. Kingsmore, Pietro Maffei, Jan D. Marshall, and Neil A. Miller
Subjects: Adult, Adolescent, Hearing loss, Ciliopathy, Cardiomyopathy, Cell Cycle Proteins, ALMS1, Alström Syndrome, SNV, Alstrom Syndrome, Child, Exons, Humans, Pedigree, Proteins, Young Adult, Mutation, Genetics, Genetics (clinical), Biology, medicine.disease_cause, Article, medicine, Type 2 Diabetes Mellitus, medicine.disease, Mutation testing, Allelic heterogeneity, medicine.symptom, Alström syndrome
Abstract: Alström Syndrome, a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multi-system involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of Alström Syndrome. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with Alström Syndrome, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.
Published: 2015
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33. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

Author: Marie-Paule Gelle, Reynaldo Antequera, Hélène Dollfus, Marie-Claude Cholette, Supawich Morkmued, Marzena Switala, Geert Mortier, Louis-Frédéric Jacquelin, Isabelle Bailleul-Forestier, Frédéric Obry, Jean Louis Raymond, Mathilde Huckert, Véronique Geoffroy, Agnès Bloch-Zupan, François Clauss, Wim Van Hul, Oana Caluseriu, Corinne Stoetzel, Marie-Cécile Manière, Joseph Hemmerlé, Jean-Luc Weickert, Virginie Laugel-Haushalter, Alain Verloes, Jean-Louis Coeuriot, Eveline Boudin, Sylvie Soskin, Ross McLeod, Pascal Dollé, Yves Alembik, Megana K. Prasad, Jean Muller, Eric Mathieu, Branka Dabovic, Annelies Dheedene, Daniel B. Rifkin, and Débora Romeo Bertola
Subjects: Male, Amelogenesis Imperfecta, DNA Mutational Analysis, medicine.disease_cause, AMELOBLASTS, ACTIVATION, Consanguinity, Mice, 0302 clinical medicine, Medicine and Health Sciences, Amelogenesis imperfecta, Child, Frameshift Mutation, Genetics (clinical), Sequence Deletion, Genetics, Mice, Knockout, 0303 health sciences, Mutation, ABNORMALITIES, DEFECTS, General Medicine, Articles, Phenotype, Pedigree, Chemistry, DIFFERENTIATION, Knockout mouse, Female, Ameloblast, FORM, EXPRESSION, (LTBP)-3 NULL MICE, Adolescent, Mutation, Missense, Biology, Osteochondrodysplasias, TOOTH, Frameshift mutation, 03 medical and health sciences, stomatognathic system, medicine, Animals, Humans, Molecular Biology, Genetic Association Studies, 030304 developmental biology, Base Sequence, Genetic heterogeneity, Biology and Life Sciences, 030206 dentistry, medicine.disease, Mice, Inbred C57BL, Radiography, stomatognathic diseases, Odontoblast, Latent TGF-beta Binding Proteins, Human medicine
Abstract: Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.
Published: 2015

34. Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

Author: Henry Houlden, Thomas Jaworek, Yvonne C Anderson, Rudy J. Richardson, Sarah Hull, Louise C. Gregory, Saima Riazuddin, Thomas M. Morgan, Joshua Hersheson, Craig Jefferies, Gavin Arno, Anthony T. Moore, Abi Li, Hélène Dollfus, Corinne Stoetzel, Christi M. Willen, Juan Pedro Martinez-Barbera, Robert A. Sisk, Megana K. Prasad, Mehul T. Dattani, Gregory A. Grabowski, Cynthia A. Prows, Rashmi S. Hegde, Tamas Revesz, John K. Fink, Zubair M. Ahmed, Robert B. Hufnagel, Klaus Dieterich, Vincent Plagnol, Laura Krueger, Taosheng Huang, and Nichole D. Hein
Subjects: Central Nervous System, Retinal degeneration, medicine.medical_specialty, Pathology, Pituitary disorder, Developmental Disabilities, Molecular Sequence Data, Hypertrichosis, Embryonic Development, Dwarfism, Neuropathy target esterase, Biology, Article, Retina, Bardet–Biedl syndrome, Intellectual Disability, Internal medicine, Genetics, medicine, Cerebellar Degeneration, Animals, Blepharoptosis, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Trichomegaly, Alleles, Zebrafish, Genetics (clinical), Laurence-Moon Syndrome, Gene Expression Regulation, Developmental, medicine.disease, Protein Structure, Tertiary, Phenotype, Endocrinology, Phospholipases, Mutation, Spinocerebellar ataxia, biology.protein, Laurence–Moon syndrome, medicine.symptom, Carboxylic Ester Hydrolases, Retinitis Pigmentosa
Abstract: Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhauser syndromes. Discovery of these additional PNPLA6 -opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
Published: 2014
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35. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Author: Montserrat Rodríguez-Ballesteros, Laurence Faivre, Pierre-Simon Jouk, Christine Francannet, Damien Sanlaville, Sophie Naudion, Hélène Dollfus, Nicole Philip, Pierre Sarda, Marine Legendre, X. Piguel, Alice Masurel-Paulet, Marie-Ange Delrue, Frédéric Bilan, Aurélia Jacquette, Dominique Bonneau, Catherine Vincent-Delorme, Valérie Layet, Michèle Mathieu-Dramard, Delphine Héron, Sébastien Moutton, Alice Goldenberg, Sophie Julia, Sophie Blesson, Sylvie Odent, Philippe Parent, Chloé Quélin, Estelle Colin, Mélanie Fradin, Anne-Marie Guerrot, David Geneviève, Lucile Pinson, Renaud Touraine, Sabine Sigaudy, Stéphanie Ragot, Didier Lacombe, Massimiliano Rossi, Salima El Chehadeh, Tiffany Busa, Annick Toutain, Stanislas Lyonnet, Véronique Abadie, Bruno Leheup, Dominique Martin-Coignard, Tania Attié-Bitach, Brigitte Gilbert-Dussardier, Sandra Mercier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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), Centre Hospitalier Le Mans (CH Le Mans), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, 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), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Endocrinologie [CHU Poitiers], Service Génétique Médicale [CHU Poitiers], French Ministry of Health ID-RCB: 2010-A00700-39, Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), 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 ), 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 Médecine Aérospatiale du Service de Santé des Armées ( IMASSA ), Service de Santé des Armées, Université d'Angers ( UA ) -CHU Angers, Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-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, Hôpital Bretonneau-CHRU Tours, Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique médicale et cytogénétique [Le Mans], CH Le Mans, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CLAD Ouest, Centre Hospitalier Universitaire [Rennes], 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 ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, CHU - HÔTEL-DIEU Clermont-Ferrand, CHU Bordeaux [Bordeaux], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Cardiologie, Pôle DUNE, CHU de Poitiers, Centre d' investigation clinique-plurithématique du CHU de Poitiers, Génétique Médicale, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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 ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, université de Bourgogne, GAD, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Central Nervous System, Male, update, Choanal atresia, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Gastroenterology, spectrum, Cohort Studies, CHARGE syndrome, Genotype, Medicine, Child, Genetics (clinical), Coloboma, Genetic disorder, Cranial Nerves, Hypoplasia, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, Child, Preschool, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Anosmia, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, otorhinolaryngologic diseases, Humans, Abnormalities, Multiple, Genetic Testing, Alleles, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, association, DNA Helicases, Infant, medicine.disease, mutations, diagnostic-criteria, 030104 developmental biology, Amino Acid Substitution, Atresia, chd7 gene, proposal, CHARGE Syndrome, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
Published: 2017
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36. Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations: a multicentric genotype-phenotype study

Author: A. Mallet, Hélène Dollfus, Marie-Cécile Manière, E. Consolino, E. Sfeir, Agnès Bloch-Zupan, Nicole Philip, François Clauss, Karen Niederreither, Sophie Jung, Megana K. Prasad, B. Noueiri, Nicolas Chassaing, Smail Hadj-Rabia, C. Tardieu, 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), 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), and 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)
Subjects: 0301 basic medicine, Adult, Pathology, medicine.medical_specialty, Heterozygote, Adolescent, Ectoderm, Mandible, Biology, Gene mutation, Compound heterozygosity, bone, dental phenotype, Sciences du Vivant [q-bio]/Génétique, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetics, medicine, Humans, oligodontia, Child, Gene, Genetics (clinical), Genetic Association Studies, Homozygote, Wnt signaling pathway, Cone-Beam Computed Tomography, Middle Aged, medicine.disease, Phenotype, 3. Good health, Wnt Proteins, Hypodontia, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dysplasia, Mutation, WNT10A mutation, Tooth, 030217 neurology & neurosurgery, extra-ectodermal signs
Abstract: WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia (TOODD) and Schöpf-Schulz-Passarge Syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared to homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations. journal article 2017 Jan 20 2017 01 20 imported
Published: 2017
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37. Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature

Author: Hélène Dollfus, Stéphane Triau, Sophie Scheidecker, Karl-Heinz Grzeschik, Estelle Colin, Laura Mary, Monique Kohler, Anne-Lise Delezoide, Elisabeth Auberger, Maria Cristina Antal, Marion Gérard, Maria-Paola Lombardi, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Reproduction & Development (AR&D), Human Genetics, Other Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Cardiovascular Sciences, and ACS - Pulmonary hypertension & thrombosis
Subjects: 0301 basic medicine, Male, Genotype, DNA Mutational Analysis, Anterior wall, Autopsy, Prenatal diagnosis, Ultrasonography, Prenatal, 03 medical and health sciences, Fetus, Prenatal Diagnosis, Genetics, medicine, Humans, Prenatal, Genetic Testing, Genetics (clinical), Genetic Association Studies, Genetic testing, Ultrasonography, medicine.diagnostic_test, Growth retardation, business.industry, Induced, Abortion, Membrane Proteins, Abortion, Induced, Anatomy, medicine.disease, Focal dermal hypoplasia, 3. Good health, Diaphragm (structural system), Focal Dermal Hypoplasia, Radiography, 030104 developmental biology, Phenotype, Mutation, Female, business, Acyltransferases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.
Published: 2017
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38. Homozygous truncating variants in TBC1D23 cause pontocerebellar hypoplasia and alter cortical development

Author: H.H. Ropers, Hélène Dollfus, Arjan P.M. de Brouwer, Frédéric Tran Mau-Them, Patrick Nitchké, Karen Runge, Jamel Chelly, Sheikh Riazuddin, Hans van Bokhoven, Saima Riazuddin, Hossein Najmabadi, Elise Schaefer, Attia Razzaq, Kimia Kahrizi, Zafar Iqbal, Jean-François Deleuze, Bénédicte Gérard, Anne de Saint Martin, Marie Aude Spitz, Ekaterina L. Ivanova, Mary Laura, Maria Victoria Hinckelmann, Nathalie Drouot, Muhammad Zaman Khan Assir, Vincent Laugel, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), University of Maryland [Baltimore], University of Social Welfare and Rehabilitation Sciences [Tehran], CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Radboud University Medical Center [Nijmegen], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Male, Microcephaly, Cerebellum, GTPase-activating protein, Developmental Disabilities, medicine.disease_cause, Mice, Neuroblastoma, 0302 clinical medicine, small normally proportioned cerebellum, microcephaly, Child, Genetics (clinical), Cells, Cultured, Genetics, Neurons, Mutation, TBC1D23, GTPase-Activating Proteins, Homozygote, Hypoplasia, Pedigree, medicine.anatomical_structure, Child, Preschool, Female, Protein family, Adolescent, Neuronal Outgrowth, Pontocerebellar hypoplasia, Biology, Nervous System Malformations, Article, 03 medical and health sciences, Cerebellar Diseases, Intellectual Disability, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], pontocerebellar hypoplasia, medicine.disease, Embryo, Mammalian, 030104 developmental biology, Rab, 030217 neurology & neurosurgery
Abstract: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.
Published: 2017
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39. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Author: Matthieu P. Robert, Salima El Chehadeh, Geert Vandeweyer, Candace Bensignor, Wilhelmina S. Kerstjens-Frederikse, Darina Prchalova, Hélène Dollfus, Jean-Baptiste Rivière, Christel Thauvin-Robinet, Paul Kuentz, Edwin Reyniers, Patrick Calvas, Caroline Bonnet, Marketa Havlovicova, Rodica Isaiko, Vincent Laugel, Nicolas Chassaing, Julien Thevenon, Christian Gilissen, Morgane Straub, Laurence Faivre, Yannis Duffourd, Miroslava Hancarova, Bart Loeys, R. Frank Kooy, Ange-Line Bruel, Rolph Pfundt, Catherine Creuzot-Garcher, Jolien S. Klein Wassink-Ruiter, Zdenek Sedlacek, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Service de pédiatrie (CHU de Dijon), Service d'Ophtalmologie (CHU de Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, 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), FHU TRANSLAD (CHU de Dijon), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Service de Cardiologie, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, MESH: Heart Defects, Congenital / physiopathology, Microcephaly, Pathology, MESH: Heart Defects, Congenital / genetics, MESH: Exome / genetics, 030105 genetics & heredity, MESH: RNA Splicing / genetics, Microphthalmia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Exome, MESH: RNA Splicing Factors / genetics, Child, Frameshift Mutation, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Exome sequencing, Coloboma, MESH: Frameshift Mutation, High-Throughput Nucleotide Sequencing, Microdeletion syndrome, Microcephaly, Verheij syndrome, PUF60, Chemistry, Phenotype, Child, Preschool, DISEASES, Medical genetics, Female, RNA Splicing Factors, medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 8, MESH: Dwarfism / genetics, Heart Defects, Congenital, medicine.medical_specialty, GENES, Adolescent, RNA Splicing, MESH: Chromosome Deletion, Dwarfism, Biology, MESH: Phenotype, Short stature, Article, PUF60, 03 medical and health sciences, Internal medicine, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Genetics, medicine, Humans, Craniofacial, MESH: Adolescent, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MESH: Humans, MESH: Child, Preschool, medicine.disease, MESH: Repressor Proteins / genetics, MESH: Male, Repressor Proteins, 030104 developmental biology, Endocrinology, MESH: Chromosomes, Human, Pair 8 / genetics, MESH: Dwarfism / physiopathology, MESH: Intellectual Disability / physiopathology, Human medicine, MESH: Intellectual Disability / genetics, Verheij syndrome, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Item does not contain fulltext Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.
Published: 2017
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40. Neural Tube Defects: The Experience of the Registry of Congenital Malformations of Alsace, France, 1995-2009

Author: Véronique Lindner, Luc Marcellin, B. Viville, Dana Timbolschi, Hélène Dollfus, Béatrice Dott, Romain Favre, Françoise Girard-Lemaire, Elisabeth Flori, Bernard Gasser, Dominique Astruc, Pierre Kehrli, Bérénice Doray, M. Kohler, Israël Nisand, Delphine Fattori, Elise Schaefer, and Bondo Monga
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Embryology, medicine.medical_specialty, Pediatrics, Population, Context (language use), Prenatal diagnosis, Pregnancy, Prenatal Diagnosis, Epidemiology, Anencephaly, Prevalence, medicine, Humans, Radiology, Nuclear Medicine and imaging, Neural Tube Defects, Registries, education, Retrospective Studies, education.field_of_study, business.industry, Spina bifida, Obstetrics and Gynecology, Retrospective cohort study, General Medicine, medicine.disease, Pediatrics, Perinatology and Child Health, Female, France, business
Abstract: Context and Objective: Considering the lack of accurate and up-to-date information available about neural tube defects (NTDs) in France, the purpose of this study was to review clinical and epidemiological data of NTDs and to evaluate the current efficiency of prenatal diagnosis in Alsace (northeastern France). Methods: A population-based retrospective study was performed from data of the Registry of Congenital Malformations of Alsace between 1995 and 2009. Data were analyzed as a whole and according to the anatomical type of the malformation (anencephaly, cephalocele and spina bifida). Statistical analyses were carried out using the Statistical Package for the Social Sciences. Results: 272 NTDs were recorded divided in 113 cases of anencephaly (42%), 35 cases of cephalocele (13%) and 124 cases of spina bifida (45%). The total prevalence at birth of 14/10,000 (95% CI 13-16) was stable throughout the reporting period. A chromosome abnormality was identified in 27 cases (12% of all karyotyped cases). NTDs were prenatally diagnosed by ultrasound in 88% of the cases. The mean age upon prenatal diagnosis slightly declined during the 15-year period, significantly for spina bifida only. The global rate of terminations of pregnancy following prenatal diagnosis was 97% (230/238). Conclusion: This work constitutes a unique population-based study providing accurate and specific up-to-date data from a unique center over a longer period (1995-2009). The most important information concerns the high and stable prevalence, which calls into question the efficiency of the primary prevention by folic acid supplementation and the efficiency of prenatal diagnosis.
Published: 2014
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41. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author: Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge
Subjects: Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract: Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
Published: 2014

42. The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach

Author: Evgeny Nudler, Vladimir Svetlov, Hélène Dollfus, Ulrich Stelzl, Thomas Walz, Daniel P. Farrell, Susan Roehl White, Jonathan Woodsmith, Luise Apelt, Frank DiMaio, Jaclyn S. Goldstein, Jean Muller, Zixuan Li, Maxence V. Nachury, Andrew R. Nager, and Hui-Ting Chou
Subjects: Models, Molecular, Conformational change, BBSome, Protein Conformation, Mass Spectrometry, Retina, Article, 03 medical and health sciences, Structural Biology, Animals, Homeostasis, Humans, Small GTPase, Molecular Biology, Structural approach, 030304 developmental biology, 0303 health sciences, ADP-Ribosylation Factors, Chemistry, Cilium, Cryoelectron Microscopy, 030302 biochemistry & molecular biology, Membrane composition, Biophysics, Cattle, Protein Multimerization, Microtubule-Associated Proteins
Abstract: The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.
Published: 2019
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43. The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family

Author: Jean-Paul Saraiva, Kinga M. Bujakowska, Hélène Dollfus, Florian Sennlaub, Shomi S. Bhattacharya, Hoan Nguyen, José-Alain Sahel, Tien D. Luu, Isabelle Audo, Marie-Elise Lancelot, Olivier Poch, Saddek Mohand-Said, Thierry Léveillard, Christelle Michiels, Aline Antonio, Mélanie Letexier, Elise Orhan, Xavier Guillonneau, Michel Paques, Christina Zeitz, Olivier Goureau, Said El Shamieh, Institut des Maladies Rares (France), Retina France, Fondation Voir et Entendre, Foundation Fighting Blindness, and Agence Nationale de la Recherche (France)
Subjects: Male, Candidate gene, Genotype, Mutation, Missense, Biology, Retina, Amyloid beta-Protein Precursor, Retinal Dystrophies, Genetics, medicine, Humans, Integral membrane protein 2B, Exome, education, Molecular Biology, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Aged, education.field_of_study, Membrane Glycoproteins, Genetic heterogeneity, Sequence Analysis, DNA, General Medicine, Middle Aged, Phenotype, medicine.anatomical_structure, Dementia, Female, Candidate Disease Gene
Abstract: Audo, Isabelle et al., Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders for which a significant number of cases remain genetically unresolved. Increasing knowledge on underlying pathogenic mechanisms with precise phenotype-genotype correlation is, however, critical for establishing novel therapeutic interventions for these yet incurable neurodegenerative conditions. We report phenotypic and genetic characterization of a large family presenting an unusual autosomal dominant retinal dystrophy. Phenotypic characterization revealed a retinopathy dominated by inner retinal dysfunction and ganglion cell abnormalities. Whole-exome sequencing identified a missense variant (c.782A>C, p.Glu261Ala) in ITM2B coding for Integral Membrane Protein 2B, which co-segregates with the disease in this large family and lies within the 24.6 Mb interval identified by microsatellite haplotyping. The physiological role of ITM2B remains unclear and has never been investigated in the retina. RNA in situ hybridization reveals Itm2b mRNA in inner nuclear and ganglion cell layers within the retina, with immunostaining demonstrating the presence of the corresponding protein in the same layers. Furthermore, ITM2B in the retina co-localizes with its known interacting partner in cerebral tissue, the amyloid ß precursor protein, critical in Alzheimer disease physiopathology. Interestingly, two distinct ITM2B mutations, both resulting in a longer protein product, had already been reported in two large autosomal dominant families with Alzheimer-like dementia but never in subjects with isolated retinal diseases. These findings should better define pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies., The project was supported by GIS-maladies rares (C.Z.), Retina France (part of the 100-Exome Project) (I.A., J.-A.S. and C.Z.), Foundation Voir et Entendre (C.Z.), Foundation Fighting Blindness (FFB) grant CD-CL-0808-0466-CHNO (I.A. and the CIC503, recognized as an FFB centre), FFB grant C-CMM-0907-0428-INSERM04, Ville de Paris and Region Ile de France and by the French State programme ‘Investissements d’Avenir’ managed by the Agence Nationale de la Recherche (LIFESENSES: ANR-10-LABX-65)
Published: 2013
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44. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

Author: Hélène Dollfus, Susanne Kohl, Maxime Hebrard, Philippe Brabet, Isabelle Meunier, Audrey Sénéchal, Elfride De Baere, Carmen Ayuso García, Christina Zeitz, Béatrice Bocquet, Sandro Banfi, Guylène Le Meur, Claire Marie Dhaenens, Delphine Allorge, Frans P.M. Cremers, Francesca Simonelli, Michel Weber, Joe G. Hollyfield, Saddek Mohand-Said, Christian P. Hamel, Gaël Manes, Marta Corton, Xavier Zanlonghi, Robert K. Koenekoop, Gilles Labesse, Almudena Avila-Fernandez, José-Alain Sahel, Isabelle Audo, Manes, G, Meunier, I, Avila Fernández, A, Banfi, Sandro, Le Meur, G, Zanlonghi, X, Corton, M, Simonelli, Francesca, Brabet, P, Labesse, G, Audo, I, Mohand Said, S, Zeitz, C, Sahel, Ja, Weber, M, Dollfus, H, Dhaenens, Cm, Allorge, D, De Baere, E, Koenekoop, Rk, Kohl, S, Cremers, Fp, Hollyfield, Jg, Sénéchal, A, Hebrard, M, Bocquet, B, Ayuso García, C, and Hamel, Cp
Subjects: Adult, Male, Proband, Genetics and epigenetic pathways of disease [NCMLS 6], genetic structures, Fundus Oculi, Molecular Sequence Data, Inheritance Patterns, Vitelliform macular dystrophy, Biology, Interphotoreceptor matrix, medicine.disease_cause, Compound heterozygosity, Young Adult, Report, medicine, Genetics, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genetics(clinical), Amino Acid Sequence, Eye Proteins, Genetics (clinical), Extracellular Matrix Proteins, Mutation, Base Sequence, Genetic heterogeneity, Middle Aged, Macular dystrophy, medicine.disease, eye diseases, Pedigree, Vitelliform Macular Dystrophy, Phenotype, Female, Proteoglycans, sense organs, Retinal Dystrophies
Abstract: Item does not contain fulltext Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507( *)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.
Published: 2013
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45. Mutations inWNT10Aare frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

Author: Encarna Guillén-Navarro, Sabine Sigaudy, Christine Coubes, Ghislaine Plessis, Dominique Martin-Coignard, Marc Abramowicz, Philippe Jonveaux, Catherine Vincent-Delorme, Frédéric Vaysse, Isabelle Bailleul-Forestier, Estelle Colin, V. Gaston, Nicolas Chassaing, Didier Lacombe, Bénédicte Demeer, Muriel Holder-Espinasse, Patrick Calvas, Julie Plaisancié, Hélène Dollfus, Eric Bieth, Alain Verloes, and Laurence Faivre
Subjects: Male, Ectodermal dysplasia, Genotype, Molecular Sequence Data, medicine.disease_cause, Compound heterozygosity, Ectodermal Dysplasia, Genetics, medicine, Humans, Amino Acid Sequence, Hypohidrotic ectodermal dysplasia, Genetic Association Studies, Genetics (clinical), Anodontia, Mutation, EDARADD, Edar Receptor, Genetic heterogeneity, business.industry, medicine.disease, Wnt Proteins, Hypodontia, Phenotype, Female, Ectodysplasin A, business, Sequence Alignment
Abstract: Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED. © 2013 Wiley Periodicals, Inc.
Published: 2013
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46. Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness

Author: Béatrice Bocquet, Hoan Nguyen, Odile Lecompte, Sharon B. Schwartz, José-Alain Sahel, Marion Neuillé, Jean-Paul Saraiva, Isabelle Audo, Samuel G. Jacobson, Olivier Poch, Kinga M. Bujakowska, Elise Orhan, Marie-Elise Lancelot, Tien D. Luu, Aline Antonio, Hélène Dollfus, Florian Sennlaub, Christelle Michiels, Shomi S. Bhattacharya, Claire Audier, Christian P. Hamel, Mélanie Letexier, Christina Zeitz, Susanne Kohl, and Xavier Zanlonghi
Subjects: Male, genetic structures, Nonsense mutation, Biology, Retina, Night Blindness, Report, Retinitis pigmentosa, medicine, Myopia, Genetics, Missense mutation, Humans, Exome, Genetics(clinical), Genetics (clinical), TRPM1, Exome sequencing, Congenital stationary night blindness, Polymorphism, Genetic, Membrane Proteins, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, Middle Aged, medicine.disease, eye diseases, Mutation, Female, sense organs, Erg
Abstract: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983GA [p.Cys328Tyr]) and a nonsense mutation (c.1318CT [p.Arg440(∗)]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151CG [p.Ser384(∗)]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs(∗)59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated.
Published: 2013
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47. Long-Term Follow-Up and Molecular Characterization of a Patient with a RECQL4 Mutation Spectrum Disorder

Author: Dan Lipsker, C. Perrigouard, B. Aral, Elisabeth Flori, Jean Muller, Hélène Dollfus, Eric Frouin, Corinne Stoetzel, C. Merklen-Djafri, Bérénice Doray, and Mélanie Fradin
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Time Factors, Long term follow up, Hyperkeratosis, Limb Deformities, Congenital, Anal Canal, Dwarfism, Dermatology, Heart Septal Defects, Atrial, Young Adult, medicine, Humans, Abnormalities, Multiple, Rapadilino syndrome, Spectrum disorder, Child, Rothmund–Thomson syndrome, Anodontia, Leukoplakia, RecQ Helicases, business.industry, Infant, Newborn, Rothmund-Thomson Syndrome, Cancer, Alopecia, Keratosis, Patella, medicine.disease, Pedigree, Radius, Thumb, Mutation, Mutation (genetic algorithm), business, Pigmentation Disorders
Abstract: The follow-up of a man from birth to adulthood, presenting with features both of RAPADILINO and Rothmund-Thomson syndrome (RTS), is described. Molecular studies confirmed the presence of two different mutations, c.2767_2768delTT and c.3061C>T, in the RECQL4 gene. This gene is known to be causative of a spectrum including Baller-Gerold syndrome, RAPADILINO syndrome and RTS. New and rare features such as oral leukoplakia and very prominent hyperkeratotic verrucous papules on both soles are shown. This patient has to date no cancer history despite bearing a truncating mutation at the age of 21 years, which is also unusual.
Published: 2013
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48. A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi

Author: Sophie Scheidecker, Hélène Dollfus, Philippe Hammann, Johan-Owen De Craene, Séverine Bär, Isabelle Perrault, Johana Chicher, Véronique Geoffroy, Christelle Etard, Kirsley Chennen, Corinne Stoetzel, Sylvie Friant, Jennifer R. Reck, Uwe Strähle, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), FRC 1589 Institut de Biologie Moléculaire et Cellulaire, and Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, General Physics and Astronomy, Golgi Apparatus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Ciliopathies, Craniofacial Abnormalities, 0302 clinical medicine, Golgi, Renal Insufficiency, 10. No inequality, Child, Cells, Cultured, Zebrafish, Skin, Multidisciplinary, Learning Disabilities, Disease genetics, Cilium, Cell biology, Mechanisms of disease, Child, Preschool, symbols, Female, Hand Deformities, Congenital, Retinitis Pigmentosa, Life sciences, biology, Adolescent, Protein subunit, Science, Mutation, Missense, Saccharomyces cerevisiae, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Vacuolar Sorting Protein VPS15, 03 medical and health sciences, symbols.namesake, Young Adult, Intraflagellar transport, ddc:570, medicine, Animals, Humans, Abnormalities, Multiple, Cilia, Ciliogenesis, Siblings, General Chemistry, Golgi apparatus, Fibroblasts, medicine.disease, Ciliopathy, 030104 developmental biology, Membrane protein, Case-Control Studies, Mutation, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells. Moreover, in VPS15-R998Q patient fibroblasts, the intraflagellar transport protein IFT20 is not localized to vesicles trafficking to the cilium but is restricted to the Golgi. Our findings suggest that at the Golgi, VPS15 and GM130 form a protein complex devoid of VPS34 to ensure the IFT20-dependent sorting and transport of membrane proteins from the cis-Golgi to the primary cilium., VPS15 is known as a VPS34-associated protein that functions in intracellular trafficking and autophagy. Here the authors identify a role for VPS15 in ciliopathy and ciliary phenotypes, and show that it interacts with GM130 and functions in IFT20-dependent cis-Golgi to cilium trafficking.
Published: 2016
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49. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes

Author: M El Alloussi, Megana K. Prasad, Hélène Dollfus, S Laouina, and Agnès Bloch-Zupan
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Genotype, Amelogenesis Imperfecta, Nonsense mutation, Consanguinity, 030105 genetics & heredity, Biology, Autoantigens, 03 medical and health sciences, Molecular genetics, medicine, Humans, Amelogenesis imperfecta, General Dentistry, Genetics, Genetic heterogeneity, Amelogenesis, Non-Fibrillar Collagens, medicine.disease, Phenotype, 3. Good health, Pedigree, Morocco, 030104 developmental biology, Codon, Nonsense, Female
Abstract: Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.
Published: 2016

50. Mutations in the ERCC2 (XPD) gene associated with severe fetal ichthyosis and dysmorphic features

Author: Marguerite, Miguet, Julien, Thevenon, Vincent, Laugel, Mathilde, Lefebvre, Aurélie, Bourchany, Jean-Baptiste, Rivière, Yannis, Duffourd, Elise, Schaefer, Maria Cristina, Antal, Rosalie, Abida, Anne-Sophie, Weingertner, Valérie, Kremer, Pierre, Vabres, Fanny, Morice-Picard, Marie, Gonzales, Dan, Lipsker, Sylvie, Fraitag, Jean-Louis, Mandel, Jamel, Chelly, Hélène, Dollfus, Laurence, Faivre, Christel, Thauvin-Robinet, Nadège, Calmels, and Salima, El Chehadeh
Subjects: Craniofacial Abnormalities, Male, Pregnancy, Mutation, Humans, Ichthyosis, Trichothiodystrophy Syndromes, Female, Gestational Age, Fetal Death, Xeroderma Pigmentosum Group D Protein
Published: 2016

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