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1. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet–Biedl syndrome: phase 3 trial results

Author: Elizabeth Forsythe, Robert M. Haws, Jesús Argente, Philip Beales, Gabriel Á. Martos-Moreno, Hélène Dollfus, Costel Chirila, Ari Gnanasakthy, Brieana C. Buckley, Usha G. Mallya, Karine Clément, and Andrea M. Haqq
Subjects: BBS, Genetic obesity, IWQOL-Lite, PedsQL, Quality of life, Setmelanotide, Medicine
Abstract: Abstract Background Bardet–Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet–Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet–Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522). Methods Patients with Bardet–Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged
Published: 2023
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2. Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Author: Agnes Bloch-Zupan, Tristan Rey, Alexandra Jimenez-Armijo, Marzena Kawczynski, Naji Kharouf, O-Rare consortium, Muriel de La Dure-Molla, Emmanuelle Noirrit, Magali Hernandez, Clara Joseph-Beaudin, Serena Lopez, Corinne Tardieu, Béatrice Thivichon-Prince, ERN Cranio Consortium, Tatjana Dostalova, Milan Macek, International Consortium, Mustapha El Alloussi, Leila Qebibo, Supawich Morkmued, Patimaporn Pungchanchaikul, Blanca Urzúa Orellana, Marie-Cécile Manière, Bénédicte Gérard, Isaac Maximiliano Bugueno, Virginie Laugel-Haushalter, Yves Alembik, Victorin Ahossi, Isabelle Bailleul-Forestier, Isabelle Blanchet, Ariane Berdal, Marie José Boileau, Nicolas Chassaing, François Clauss, Caroline Delfosse, Anne De-Saint-Martin, Jean-Christophe Dahlet, Bérénice Doray, Jean-Luc Davideau, Tiphaine Davit-Béal, Hélène Dollfus, Jean-Pierre Duprez, Muriel de La Dure Molla, Klauss Dieterich, Dominique Droz, Salima El Chehadeh, Olivier Etienne, Edouard Euvrard, Laurence Faivre, Benjamin Fournier, Elsa Garot, Bruno Grollemund, Nathalie Guffon-Fouilhoux, Mathilde Huckert, Bertand Isidor, Sophie Jung, Didier Lacombe, Alinoe Lavillaurex, Marine Lebrun, Bruno Leheup, Adeline Loing, Sandrine Marlin, Jean-Jacques Morrier, Michèle Muller-Bolla, Sylvie Odent, Marie Paule Gelle, Juliette Piard, Linda Pons, Béatrice Richard, Massimiliano Rossi, Prune Sadones, Elise Schaefer, Jean-Louis Sixou, Sylvie Soskin, Marion Strub, Annick Toutain, Alain Verloes, Frédéric Vaysse, and Delphine Wagner
Subjects: enamel, amelogenesis imperfecta, genetics, rare diseases, NGS, next-generation sequencing, Physiology, QP1-981
Abstract: Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.
Published: 2023
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3. Characterization of SSBP1-related optic atrophy and foveopathy

Author: Isabelle Meunier, Béatrice Bocquet, Sabine Defoort-Dhellemmes, Vasily Smirnov, Carl Arndt, Marie Christine Picot, Hélène Dollfus, Majida Charif, Isabelle Audo, Hélèna Huguet, Xavier Zanlonghi, and Guy Lenaers
Subjects: Medicine, Science
Abstract: 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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4. Cystoid maculopathy is a frequent feature of Cohen syndrome-associated retinopathy

Author: Pierre-Henry Gabrielle, Laurence Faivre, Isabelle Audo, Xavier Zanlonghi, Hélène Dollfus, Alberta A. H. J. Thiadens, Christina Zeitz, Grazia M. S. Mancini, Yaumara Perdomo, Saddek Mohand-Saïd, Eléonore Lizé, Vincent Lhussiez, Emeline F. Nandrot, Niyazi Acar, Catherine Creuzot-Garcher, José-Alain Sahel, Muhammad Ansar, Christel Thauvin-Robinet, Laurence Duplomb, and Romain Da Costa
Subjects: Medicine, Science
Abstract: 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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5. The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Author: Graeme C. Black, Panagiotis Sergouniotis, Andrea Sodi, Bart P. Leroy, Caroline Van Cauwenbergh, Petra Liskova, Karen Grønskov, Artur Klett, Susanne Kohl, Gita Taurina, Marius Sukys, Lonneke Haer-Wigman, Katarzyna Nowomiejska, João Pedro Marques, Dorothée Leroux, Frans P. M. Cremers, Elfride De Baere, Hélène Dollfus, and ERN-EYE study group
Subjects: Genetic and genomic testing, Rare eye diseases, ERN-EYE, Position statement, Medicine
Abstract: Abstract Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.
Published: 2021
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6. The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol

Author: Catherine Lejeune, Charley Robert-Viard, Nicolas Meunier-Beillard, Myriam Alice Borel, Léna Gourvès, Stéphanie Staraci, Anne-Laure Soilly, Francis Guillemin, Valerie Seror, Hamza Achit, Marion Bouctot, Marie-Laure Asensio, Anne-Sophie Briffaut, Christelle Delmas, Ange-Line Bruel, Alexia Benoit, Alban Simon, Bénédicte Gerard, Hamza Hadj Abdallah, Stanislas Lyonnet, Laurence Faivre, Christel Thauvin-Robinet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Jean Muller, Yannis Duffourd, Anne Boland, Jean-François Deleuze, Hélène Espérou, Christine Binquet, and Hélène Dollfus
Subjects: intellectual disability, genome sequencing, cost-effectiveness, qualitative study, micro-costing, Genetics, QH426-470
Abstract: Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS.Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses.Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361).Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).
Published: 2022
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7. Consensus clinical management guidelines for Alström syndrome

Author: Natascia Tahani, Pietro Maffei, Hélène Dollfus, Richard Paisey, Diana Valverde, Gabriella Milan, Joan C. Han, Francesca Favaretto, Shyam C. Madathil, Charlotte Dawson, Matthew J. Armstrong, Adrian T. Warfield, Selma Düzenli, Clair A. Francomano, Meral Gunay-Aygun, Francesca Dassie, Vincent Marion, Marina Valenti, Kerry Leeson-Beevers, Ann Chivers, Richard Steeds, Timothy Barrett, and Tarekegn Geberhiwot
Subjects: Alström syndrome, Guidelines, Rare disease, Blindness, Deafness, Cardiomyopathy, Medicine
Abstract: 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
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8. Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

Author: Ariane Kröll‐Hermi, Frédéric Ebstein, Corinne Stoetzel, Véronique Geoffroy, Elise Schaefer, Sophie Scheidecker, Séverine Bär, Masanari Takamiya, Koichi Kawakami, Barbara A Zieba, Fouzia Studer, Valerie Pelletier, Carine Eyermann, Claude Speeg‐Schatz, Vincent Laugel, Dan Lipsker, Florian Sandron, Steven McGinn, Anne Boland, Jean‐François Deleuze, Lauriane Kuhn, Johana Chicher, Philippe Hammann, Sylvie Friant, Christelle Etard, Elke Krüger, Jean Muller, Uwe Strähle, and Hélène Dollfus
Subjects: cataract, deafness, neurosensory disease, proteasome, PSMC3, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract The ubiquitin–proteasome system degrades ubiquitin‐modified proteins to maintain protein homeostasis and to control signalling. Whole‐genome sequencing of patients with severe deafness and early‐onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.
Published: 2020
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9. Genome Sequencing for Genetics Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study

Author: Christine Binquet, Catherine Lejeune, Laurence Faivre, Marion Bouctot, Marie-Laure Asensio, Alban Simon, Jean-François Deleuze, Anne Boland, Francis Guillemin, Valérie Seror, Christelle Delmas, Hélène Espérou, Yannis Duffourd, Stanislas Lyonnet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Bénédicte Gerard, and Hélène Dollfus
Subjects: genome sequencing, intellectual disability, cost-effectiveness, minimal reference strategy, diagnostic odyssey, Genetics, QH426-470
Abstract: Introduction: Intellectual Disability (ID) is the most common cause of referral to pediatric genetic centers, as it affects around 1–3% of the general population and is characterized by a wide genetic heterogeneity. The Genome Sequencing (GS) approach is expected to achieve a higher diagnostic yield than exome sequencing given its wider and more homogenous coverage, and, since theoretically, it can more accurately detect variations in regions traditionally not well captured and identify structural variants, or intergenic/deep intronic putatively pathological events. The decreasing cost of sequencing, the progress in data-management and bioinformatics, prompted us to assess GS efficiency as the first line procedure to identify the molecular diagnosis in patients without obvious ID etiology. This work is being carried out in the framework of the national French initiative for genomic medicine (Plan France Médecine Génomique 2025).Methods and Analysis: This multidisciplinary, prospective diagnostic study will compare the diagnostic yield of GS trio analysis (index case, father, mother) with the French core minimal reference strategy (Fragile-X testing, chromosomal microarray analysis and Gene Panel Strategy of 44 selected ID genes). Both strategies are applied in a blinded fashion, in parallel, in the same population of 1275 ID index cases with no obvious diagnosis (50% not previously investigated). Among them, a subgroup of 196 patients are randomized to undergo GS proband analysis in addition to GS trio analysis plus the French core minimal reference strategy, in order to compare their efficiency. The study also aims to identify the most appropriate strategy according to the clinical presentation of the patients, to evaluate the impact of deployment of GS on the families’ diagnostic odyssey and the modification of their care, and to identify the advantages/difficulties for the patients and their families.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I and the French data privacy commission (CNIL, authorization 919361).Trial Registration:ClinicalTrials.gov identifier NCT04154891 (07/11/2019).
Published: 2022
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10. 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: Evidence-based precision medicine, Rare eye disease, Human phenotype ontology, Orphanet rare disease ontology, Medicine
Abstract: Abstract Background 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). Methods 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. Results 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. Conclusions 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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11. Neurotrophic Keratitis Due to Congenital Corneal Anesthesia with Deafness, Hypotonia, Intellectual Disability, Face Abnormality and Metabolic Disorder: A New Syndrome?

Author: Arvydas Gelzinis, Dovile Simonaviciute, Agne Krucaite, Luca Buzzonetti, Hélène Dollfus, and Reda Zemaitiene
Subjects: neurotrophic keratitis, neurotrophic keratopathy, congenital corneal anesthesia, corneal erosion, corneal ulcer, trigeminal nerve, Medicine (General), R5-920
Abstract: Neurotrophic keratitis is a rare degenerative disease of the cornea that can lead to corneal ulceration, scarring, and significant visual impairment. It most commonly occurs in adults and is rarely diagnosed in children. Congenital corneal anesthesia is an extremely rare condition that requires appropriate ophthalmologists’ attention in making diagnosis and treatment decisions. This condition usually presents in infancy or early childhood and is characterized by rare blinking rate, decreased tearing or a corneal ulcer that is unresponsive to treatment. In this case report, we describe a patient with multiple systemic and neurological disorders who presented to the ophthalmology department due to corneal erosion unresponsive to treatment. Brain magnetic resonance imaging confirmed bilateral trigeminal hypoplasia and the diagnosis of neurotrophic keratopathy due to bilateral congenital corneal anesthesia was made. The discrepancy between clinical signs and symptoms or treatment non-response in cases of corneal erosions should alert the ophthalmologists to suspect trigeminal dysfunction. MRI is the gold standard to confirm congenital corneal anesthesia and to differentiate from other possible neurotrophic keratitis causes.
Published: 2022
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12. Magnetically Assisted Drug Delivery of Topical Eye Drops Maintains Retinal Function In Vivo in Mice

Author: Marco Bassetto, Daniel Ajoy, Florent Poulhes, Cathy Obringer, Aurelie Walter, Nadia Messadeq, Amir Sadeghi, Jooseppi Puranen, Marika Ruponen, Mikko Kettunen, Elisa Toropainen, Arto Urtti, Hélène Dollfus, Olivier Zelphati, and Vincent Marion
Subjects: magnetic targeting, non-invasive, topical drug delivery, magnetic nanoparticles, retinal degeneration, Bardet Biedl syndrome, Pharmacy and materia medica, RS1-441
Abstract: Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs’ presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs−/− mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases.
Published: 2021
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13. Expanding phenotype of hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis caused by FAM111B mutations: Report of an additional family raising the question of cancer predisposition and a short review of early-onset poikiloderma

Author: Raphaëlle Goussot, MD, Megana Prasad, MD, Corinne Stoetzel, MD, Cédric Lenormand, MD, PhD, Hélène Dollfus, MD, PhD, and Dan Lipsker, MD, PhD
Subjects: FAM111B, inherited poikiloderma, pancreatic cancer, Dermatology, RL1-803
Published: 2017
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14. A New SLC10A7 Homozygous Missense Mutation Responsible for a Milder Phenotype of Skeletal Dysplasia With Amelogenesis Imperfecta

Author: Virginie Laugel-Haushalter, Séverine Bär, Elise Schaefer, Corinne Stoetzel, Véronique Geoffroy, Yves Alembik, Naji Kharouf, Mathilde Huckert, Pauline Hamm, Joseph Hemmerlé, Marie-Cécile Manière, Sylvie Friant, Hélène Dollfus, and Agnès Bloch-Zupan
Subjects: skeletal dysplasia, amelogenesis imperfecta, NGS (next generation sequencing), human, rare diseases, Genetics, QH426-470
Abstract: Amelogenesis imperfecta (AI) is a heterogeneous group of rare inherited diseases presenting with enamel defects. More than 30 genes have been reported to be involved in syndromic or non-syndromic AI and new genes are continuously discovered (Smith et al., 2017). Whole-exome sequencing was performed in a consanguineous family. The affected daughter presented with intra-uterine and postnatal growth retardation, skeletal dysplasia, macrocephaly, blue sclerae, and hypoplastic AI. We identified a homozygous missense mutation in exon 11 of SLC10A7 (NM_001300842.2: c.908C>T; p.Pro303Leu) segregating with the disease phenotype. We found that Slc10a7 transcripts were expressed in the epithelium of the developing mouse tooth, bones undergoing ossification, and in vertebrae. Our results revealed that SLC10A7 is overexpressed in patient fibroblasts. Patient cells display altered intracellular calcium localization suggesting that SLC10A7 regulates calcium trafficking. Mutations in this gene were previously reported to cause a similar syndromic phenotype, but with more severe skeletal defects (Ashikov et al., 2018;Dubail et al., 2018). Therefore, phenotypes resulting from a mutation in SLC10A7 can vary in severity. However, AI is the key feature indicative of SLC10A7 mutations in patients with skeletal dysplasia. Identifying this important phenotype will improve clinical diagnosis and patient management.
Published: 2019
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15. Identification and Characterization of Known Biallelic Mutations in the IFT27 (BBS19) Gene in a Novel Family With Bardet-Biedl Syndrome

Author: Elise Schaefer, Clarisse Delvallée, Laura Mary, Corinne Stoetzel, Véronique Geoffroy, Caroline Marks-Delesalle, Muriel Holder-Espinasse, Jamal Ghoumid, Hélène Dollfus, and Jean Muller
Subjects: Bardet-Biedl syndrome, IFT27 gene, BBS19, ciliopathy, whole exome sequencing, Genetics, QH426-470
Abstract: Bardet-Biedl syndrome (BBS; MIM 209900) is a rare ciliopathy characterized by retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. Mutations in 22 BBS genes have been identified to cause the disease. We report a family with typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, cognitive impairment, and atrioventricular septal defect) mutated in IFT27/BBS19. IFT27 is part of the Intraflagellar transport (IFT), a bidirectional mechanism allowing the protein motility within the cilia. Using whole exome sequencing, two compound heterozygous mutations were found in the proband (NM_006860.4:c.[104A > G];[349+1G > T], p.[Tyr35Cys];[?]) consistent with the expected autosomal recessive inheritance mode. These two mutations have already been reported but independently in other families and lacking either familial segregation or functional validation. This is the third report of IFT27 mutations in BBS patients confirming IFT27 as a BBS gene (BBS19). Mutations in IFT genes (IFT27, IFT172 and IFT74) confirm the IFT-pathway as a pathomechanism for BBS.
Published: 2019
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16. A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi

Author: Corinne Stoetzel, Séverine Bär, Johan-Owen De Craene, Sophie Scheidecker, Christelle Etard, Johana Chicher, Jennifer R. Reck, Isabelle Perrault, Véronique Geoffroy, Kirsley Chennen, Uwe Strähle, Philippe Hammann, Sylvie Friant, and Hélène Dollfus
Subjects: Science
Abstract: 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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17. Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning

Author: Virginie Laugel-Haushalter, Supawich Morkmued, Corinne Stoetzel, Véronique Geoffroy, Jean Muller, Anne Boland, Jean-François Deleuze, Kirsley Chennen, Waranuch Pitiphat, Hélène Dollfus, Karen Niederreither, Agnès Bloch-Zupan, and Patimaporn Pungchanchaikul
Subjects: rare disease, dental anomalies, patterning, mutations, NGS, human, Physiology, QP1-981
Abstract: In this study, we report a unique dominantly inherited disorganized supernumerary cusp and single root phenotype presented by 11 affected individuals belonging to 5 north-eastern Thai families. Using whole exome sequencing (WES) we identified a common single missense mutation that segregates with the phenotype in exon 6 of CACNA1S (Cav1.1) (NM_000069.2: c.[865A > G];[=] p.[Ile289Val];[=]), the Calcium Channel, Voltage-Dependent, L Type, Alpha-1s Subunit, OMIM ∗ 114208), affecting a highly conserved amino-acid isoleucine residue within the pore forming subdomain of CACNA1S protein. This is a strong genetic evidence that a voltage-dependent calcium ion channel is likely to play a role in influencing tooth morphogenesis and patterning.
Published: 2018
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18. 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: Medicine
Abstract: Professor Michael Larsen, who is a member of the ERN-EYE Ontology Study Group and co-chair of Workgroup on Retinal Rare Eye Diseases (WG1), was inadvertently omitted from the author list in the Acknowledgements section of the original article [1].
Published: 2019
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19. <scp>ROSAH</scp> syndrome mimicking chronic uveitis

Author: Christine Fardeau, Munirah Alafaleq, Claire‐Marie Dhaenens, Hélène Dollfus, Isabelle Koné‐Paut, Olivier Grunewald, Jean‐Baptiste Morel, Cherif Titah, David Saadoun, Patrice Olivier Lazeran, and Isabelle Meunier
Subjects: Genetics, Genetics (clinical)
Abstract: To suggest a unique missense variant candidate based on long-term ophthalmological changes and associated systemic signs described in five patients from two unrelated families affected by an autosomal dominant multi-systemic disorder including Retinal dystrophy, Optic nerve oedema, Splenomegaly, Anhidrosis and migraine Headaches, called ROSAH syndrome, related to a unique missense variant in ALPK1 gene. Observational longitudinal follow-up study of unrelated families. Clinical analysis of ophthalmological and systemic examinations was performed, followed by genetic analysis, including targeted Next Generation Sequencing (NGS) and Whole-Genome Sequencing (WGS). The ophthalmological phenotype showed extensive optic nerve swelling associated with early macular oedema and vascular leakage. The main associated systemic manifestations were recurrent fever, splenomegaly, anhidrosis, mild cytopenia, anicocytosis and hypersegmented polynuclear cells. WGS, shortened in the second family by the gene candidate suggestion, revealed in all patients the heterozygous missense variant c.710CT; p.(Thr237Met) in ALPK1. The primary morbidity in ROSAH syndrome in this cohort appeared ophthalmological. Comprehensive, detailed phenotype changes aided by the advancement in genetic testing could allow an early genetic diagnosis of ROSAH syndrome and targeted treatment. The unique missense variant may be suggested as a target of gene correction therapy.
Published: 2022

20. 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

21. Contribution of whole genome sequencing in the molecular diagnosis of mosaic partial deletion of the NF1 gene in neurofibromatosis type 1

Author: Laurence Pacot, Valerie Pelletier, Albain Chansavang, Audrey Briand-Suleau, Cyril Burin des Roziers, Audrey Coustier, Theodora Maillard, Nicolas Vaucouleur, Lucie Orhant, Cécile Barbance, Alban Lermine, Nadim Hamzaoui, Djihad Hadjadj, Ingrid Laurendeau, Laïla El Khattabi, Juliette Nectoux, Michel Vidaud, Béatrice Parfait, Hélène Dollfus, Eric Pasmant, and Dominique Vidaud
Subjects: Genetics, Genetics (clinical)
Published: 2022

22. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Author: Friederike Petzold, Katy Billot, Xiaoyi Chen, Charline Henry, Emilie Filhol, Yoann Martin, Marina Avramescu, Maxime Douillet, Vincent Morinière, Pauline Krug, Cécile Jeanpierre, Kalman Tory, Olivia Boyer, Anita Burgun, Aude Servais, Remi Salomon, Alexandre Benmerah, Laurence Heidet, Nicolas Garcelon, Corinne Antignac, Mohamad Zaidan, Sophie Saunier, Tania Attié-Bitach, Valerie Comier-Daire, Jean-Michel Rozet, Yaacov Frishberg, Brigitte Llanas, Michel Broyer, Nabil Mohsin, Marie-Alice Macher, Nicole Philip, Véronique Baudouin, Damian Brackman, Chantal Loirat, Marina Charbit, Maud Dehennault, Claude Guyot, Pierre Bataille, Mariet Elting, Georges Deschenes, Andrea Gropman, Geneviève Guest, Marie-France Gagnadoux, Philippe Nicoud, Pierre Cochat, Bruno Ranchin, Albert Bensman, Anne-Marie Guerrot, Bertrand Knebelmann, Ilmay Bilge, Danièle Bruno, Stéphane Burtey, Caroline Rousset Rouvière, Valérie Caudwell, Denis Morin, Hélène Dollfus, Anne Maisin, Christian Hamel, Eric Bieth, Sophie Gie, Judith Goodship, Gwenaelle Roussey, Hermine La Selve, Hubert Nivet, Lucie Bessenay, Mathilde Caillez, Jean Bernard Palcoux, Stéphane Benoît, Philippe Dubot, Marc Fila, Fabienne Giuliano, Daouya Iftene, Michele Kessler, Theresa Kwon, Anine Lahoche, Audrey Laurent, Anne-Laure Leclerc, David Milford, Thomas Neuhaus, Sylvie Odent, Philippe Eckart, Dominique Chauveau, Patrick Niaudet, Horacio Repetto, Sophie Taque, Alexandra Bruel, Alexandra Noel-Botte, Emma Allain Launay, Lisa Allard, Dany Anlicheau, Anne-Laure Adra, Arnaud Garnier, Arvind Nagra, Remy Baatard, Justine Bacchetta, Banu Sadikoglu, Christine Barnerias, Anne Barthelemy, Lina Basel, Nader Bassilios, Hedi Ben Maiz, Fatma Ben Moussa, Faïza Benmati, Romain Berthaud, Aurélia Bertholet, Dominique Blanchier, Jean Jacques Boffa, Karim Bouchireb, Ihab Bouhabel, Zakaria Boukerroucha, Guylhène Bourdat-Michel, Odile Boute, Karine Brochard, Roseline Caumes, Siham Chafai Elalaoui, Bernard Chamontin, Marie Caroline Chastang, Christine Pietrement, Christine Richer, Christophe Legendre, Karin Dahan, Fabienne Dalla-Vale, Damien Thibaudin, Maxime Dauvergne, Salandre Davourie, Martin Debeukelaer, Jean Daniel Delbet, Constantinos Deltas, Denis Graber, Nadège Devillars, Boucar Diouf, Martine Doco Fenzy, Jean-Luc André, Dominique Joly, Alan Fryer, Laetitia Albano, Elisabeth Cassuto, Aline Pincon, Ana Medeira, Annabelle Chaussenot, Anne Mensire-Marinier, Francois Bouissou, Stephane Decramer, Armand Bottani, Aurélie Hummel, Alexandre Karras, Avi Katz, Christine Azema, Bénédicte Janbon, Bernard Roussel, Claude Bonniol, Christiophe Mariat, Gérard Champion, Deborah Chantreuil, Nicolas Chassaing, Christiane Mousson, Christine Baudeau, Delphine Hafdar Cuntz, Cyril Mignot, Laurene Dehoux, Didier Lacombe, Thierry Hannedouche, Elodie Mérieau, Emmanuelle Charlin, Eric Gauthier, Florent Plasse, Stanislas Faguer, Fanny Lebas, Florence Demurger, Francesco Emma, François Cartault, Geneviève Dumont, Nathalie Godefroid, Vincent Guigonis, Sophie Hillaire, Jaap Groothoff, Jan Dudley, Noémie Jourde-Chiche, Khalil El Karoui, Saoussen Krid, Krier Coudert, Larbi Bencheick, Laurent Yver, Marie-Pierre Lavocat, Le Monies De Sagazan, Valerie Leroy, Lise Thibaudin, Liz Ingulli, Lorraine Gwanmesia, Lydie Burglen, Marie-Hélène Saïd-Menthon, Marta Carrera, Mathilde Nizon, Catherine Melander, Michel Foulard, Monique Blayo, Jacques Prinseau, Nadine Jay, Nathalie Brun, Nicolas Camille, François Nobili, Olivier Devuyst, Ouafa Ben Brahim, Paloma Parvex, Laurence Perrin Sabourin, Philippe Blanc, Philippe Vanhille, Pierre Galichon, Sophie Pierrepont, Vincent Planquois, Gwenaelle Poussard, Claire Pouteil Noble, Radia Allal, Raphaelle Bernard, Raynaud Mounet, Rémi Cahen, Renaud Touraine, Claire Rigothier, Amélie Ryckewaert, Mathieu Sacquepee, Salima El Chehadeh, Charlotte Samaille, Shuman Haq, Ari Simckes, Stéphanie Lanoiselée, Stephanie Tellier, Jean-François Subra, Sylvie Cloarec, Julie Tenenbam, Thomas Lamy, Valérie Drouin Garraud, Huguette Valette, Vanina Meyssonnier, Rosa Vargas-Poussou, Yves Snajer, Sandrine Durault, Emmanuelle Plaisier, Etienne Berard, Fadi Fakhouri, Ferielle Louillet, Paul Finielz, Michel Fischbach, Bernard Foliguet, Hélène Francois-Pradier, Florentine Garaix, Marion Gerard, Gianfranco Rizzoni, Brigitte Gilbert, Denis Glotz, Astrid Godron Dubrasquet, Jean-Pierre Grünfeld, Guillaume Bollee, Michelle Hall, Sverker Hansson, Damien Haye, Hélène Taffin, Friedhelm Hildebrandt, Maryvonne Hourmand, Hümya Kayserili, Ivan Tack, Marie Line Jacquemont, Jennifer Fabre-Teste, Cliff Kashtan, Kkoen Van Hoeck, Alexandre Klein, Yannick Knefati, Nine Knoers, Martin Konrad, Alain Lachaux, Isabelle Landru, Gilbert Landthaler, Philippe Lang, Patrick Le Pogamp, Tristan Legris, Catherine Didailler, Thierry Lobbedez, Loïc de Parscau, Lucile Pinson, Hervé Maheut, Marc Duval-Arnould, Marlène Rio, Marie-Claire Gubler, Pierre Merville, Guillaume Mestrallet, Maite Meunier, Karine Moreau, Jérôme Harambat, Graeme Morgan, Georges Mourad, Niksic Stuber, Odile Boespflug-Tanguy, Olivier Dunand, Olivier Niel, Nacera Ouali, Paolo Malvezzi, Pauline Abou Jaoude, Solenne Pelletier, Julie Peltier, M.B. Petersen, Philippe Michel, Philippe Rémy, Jean-Baptiste Philit, Valérie Pichault, Thierry Billette de Villemeur, Bernard Boudailliez, Bruno Leheup, Claire Dossier, Djamal-Dine Djeddi, Yves Berland, Bruno Hurault de Ligny, Susan Rigden, Christophe Robino, Annick Rossi, Sabine Sarnacki, Messaoud Saidani, Albane Brodin Sartorius, Elise Schäfer, Sztriha Laszlo, Marie-Christine Thouret, Angélique Thuillier-Lecouf, Howard Trachtman, Claire Trivin, Michel Tsimaratos, Rita Van Damme-Lombaerts, Marjolaine Willems, Michel Youssef, Ariane Zaloszyc, Alexis Zawodnik, and Marie-Julia Ziliotis
Subjects: Nephrology
Abstract: Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.
Published: 2023

23. 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

24. 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

25. Current management of patients with RPE65 mutation-associated Inherited Retinal Degenerations (RPE65-IRD) in Europe. Results of a 2 years follow-up multinational survey

Author: Birgit Lorenz, Joana Tavares, L. Ingeborgh van den Born, João Pedro Marques, Elisabetta Pilotto, Katarina Stingl, Peter Charbel Issa, Dorothée Leroux, Hélène Dollfus, and Hendrik P.N. Scholl
Subjects: Cellular and Molecular Neuroscience, Ophthalmology, General Medicine, Sensory Systems
Abstract: Introduction: To evaluate the current management of RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of Voretigene Neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-Eye) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. Methods: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. Results: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1 – 19/center, median 6), and 43 planned for treatment (range 0 – 10/center, median 6). The overall age range was 3 – 52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2 – 60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full field stimulus test (FST) improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. Discussion/Conclusion: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-Eye HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of two class 4 or 5 mutations on both alleles, or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers.
Published: 2023

26. 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

27. 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

28. 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

29. 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

30. WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

Author: Adella Karam, Clarisse Delvallée, Alejandro Estrada-Cuzcano, Véronique Geoffroy, Jean-Baptiste Lamouche, Anne-Sophie Leuvrey, Elsa Nourisson, Julien Tarabeux, Corinne Stoetzel, Sophie Scheidecker, Louise Frances Porter, Emmanuelle Génin, Richard Redon, Florian Sandron, Anne Boland, Jean-François Deleuze, Nicolas Le May, Hélène Dollfus, and Jean Muller
Subjects: Inorganic Chemistry, Organic Chemistry, General Medicine, Physical and Theoretical Chemistry, BBS5 gene, Bardet–Biedl syndrome, whole-genome sequencing, structural variation, primary cilium, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract: Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein’s impact was confirmed on the patient’s cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients’ genetic explorations as well as functional tests to assess a variant’s pathogenicity.
Published: 2023

31. 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

32. Response to comment on: Could internal limiting membrane peeling before Voretigen Neparvovec-ryzl subretinal injection prevent focal chorioretinal atrophy?

Author: Lea Dormegny, Fouzia Studer, Arnaud Sauer, Laurent Ballonzoli, Claude Speeg-Schatz, Tristan Bourcier, Helene Dollfus, and David Gaucher
Subjects: Science (General), Q1-390, Social sciences (General), H1-99
Published: 2024
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33. 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

34. <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

35. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Author: Jill A. Rosenfeld Mokry, Shamil R. Sunyaev, Erica E. Davis, Niki Mourtzi, Maria Kousi, Richard A. Lewis, Michael E. Talkowski, Azita Sadeghpour, Onuralp Soylemez, Maxim Y Wolf, Manolis Kellis, Nicholas Katsanis, Christopher A. Cassa, Jean Muller, Kelsey McFadden, Irwin Jungreis, Sebastian Akle, Aysegul Ozanturk, Hélène Dollfus, and Harrison Brand
Subjects: Nonsynonymous substitution, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, 0303 health sciences, education.field_of_study, Population, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, Ciliopathy, symbols.namesake, 0302 clinical medicine, medicine, Mendelian inheritance, symbols, Epistasis, Allele, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
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: 2020

36. 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

37. Contributors

Author: Tomas S. Aleman, Patrizia Amati-Bonneau, Benoît Arveiler, Jane L. Ashworth, Isabelle Audo, Giacomo M. Bacci, Nicole Balducci, Irina Balikova, Miriam Bauwens, Piero Barboni, Johannes Birtel, Susmito Biswas, Graeme C.M. Black, Catherine Blanchet, Béatrice Bocquet, Camiel J.F. Boon, Antoine Brézin, Cyril Burin des Roziers, Emma Burkitt-Wright, Michele Callea, Michele Carbonelli, Valerio Carelli, Jasmina Cehajic-Kapetanovic, Kate E. Chandler, Aman Chandra, Jill Clayton-Smith, Johanna M. Colijn, Frauke Coppieters, Catherine A. Cukras, Avril Daly, Elfride De Baere, Julie De Zaeytijd, Arundhati Dev Borman, Hélène Dollfus, Sofia Douzgou Houge, Elizabeth C. Engle, Pascal Escher, D. Gareth Evans, Kristina Teär Fahnehjelm, Christina Fasser, Mathieu Fiore, Kaoru Fujinami, Yu Fujinami-Yokokawa, Brenda L. Gallie, Michalis Georgiou, Martin Gliem, Monika K. Grudzinska Pechhacker, Georgina Hall, Wolf M. Harmening, Robert H. Henderson, Elise Héon, Nashila Hirji, Frank G. Holz, Laryssa A. Huryn, Elizabeth A. Jones, Vasiliki Kalatzis, Arif O. Khan, Ungsoo S. Kim, Caroline C.W. Klaver, Neruban Kumaran, Chiara La Morgia, Fiona Lalloo, Eulalie Lasseaux, Helena Lee, Guy Lenaers, Eva Lenassi, Bart P. Leroy, Petra Liskova, I. Christopher Lloyd, Robert E. MacLaren, Omar A. Mahroo, Alvaro J. Mejia-Vergara, Isabelle Meunier, Michel Michaelides, Anthony T. Moore, Mariya Moosajee, Fanny Morice-Picard, Francis L. Munier, Magella M. Neveu, Erin C. O'Neil, Anna Nordenström, Neil R.A. Parry, Maria I. Patrício, Manoj V. Parulekar, Dipak Ram, Simon C. Ramsden, Johane Robitaille, Anthony G. Robson, Pierre-Raphaël Rothschild, Alfredo A. Sadun, Kaspar Schuerch, Miguel C. Seabra, Jay E. Self, Panagiotis I. Sergouniotis, Fadi Shaya, Paul A. Sieving, Ine Strubbe, Francesca Simonelli, Kent W. Small, Martin P. Snead, Karolina M. Stepien, Mays Talib, Rachel L. Taylor, Francesco Testa, Alberta A.H.J. Thiadens, Elias I. Traboulsi, Viet H. Tran, Veronika Vaclavik, Sophie Valleix, Caroline Van Cauwenbergh, Kristof Van Schil, Mary C. Whitman, Colin E. Willoughby, Kanmin Xue, Jingyan Yang, Patrick Yu-Wai-Man, Christina Zeitz, and Martin Zinkernagel
Published: 2022

38. Magnetically Assisted Drug Delivery of Topical Eye Drops Maintains Retinal Function In Vivo in Mice

Author: Cathy Obringer, Vincent Marion, Amir Sadeghi, Hélène Dollfus, Marika Ruponen, Elisa Toropainen, Nadia Messadeq, Arto Urtti, Jooseppi Puranen, Mikko I. Kettunen, Daniel Ajoy, Florent Poulhes, Aurelie Walter, Marco Bassetto, and Olivier Zelphati
Subjects: Retinal degeneration, magnetic nanoparticles, topical drug delivery, Population, non-invasive, Pharmaceutical Science, Pharmacology, Article, chemistry.chemical_compound, Pharmacy and materia medica, In vivo, Sciences du Vivant [q-bio]/Biologie cellulaire, medicine, education, education.field_of_study, Retina, business.industry, small drug molecules, Retinal, unfolded protein response, medicine.disease, RS1-441, Bardet Biedl syndrome, medicine.anatomical_structure, magnetic targeting, chemistry, Targeted drug delivery, Drug delivery, retinal degeneration, Guanabenz, business, medicine.drug
Abstract: Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs’ presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs−/− mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases.
Published: 2021
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39. ODP606 Long-term Efficacy of Setmelanotide in Patients With Bardet-Biedl Syndrome

Author: Jesús Argente, Philip Beales, Karine Clément, Hélène Dollfus, Elizabeth Forsythe, Andrea Haqq, Robert Haws, Gabriel Martos-Moreno, Robert Mittleman, Jack Yanovski, Guojun Yuan, and Wendy Chung
Subjects: Endocrinology, Diabetes and Metabolism
Abstract: Objective Bardet-Biedl syndrome (BBS) is a rare genetic disease characterized by hyperphagia (pathologic insatiable hunger) and early-onset, severe obesity believed to be driven by impaired signaling in the melanocortin-4 receptor (MC4R) pathway. In a Phase 2 and a pivotal Phase 3 trial, treatment with the MC4R agonist setmelanotide produced beneficial reductions in weight, body mass index (BMI), BMI Z score, and hunger in patients with BBS at ∼1 year. The current analysis is the first to assess the continued long-term efficacy of setmelanotide administration in patients with BBS over ∼2 years. Methods Patients with BBS aged ≥6 years were eligible for this observational long-term extension (LTE) trial (NCT03651765) if they completed an index trial in which they received setmelanotide and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received up to ∼12 months of setmelanotide as part of the index trial and began the LTE immediately following completion of the index trial. Study visits occurred approximately every 3 months in the LTE trial. Study objectives included evaluating changes in body weight and assessing safety and tolerability. The current analysis reports outcomes after ∼1 year of additional setmelanotide administration during the LTE trial, relative to index trial baseline. Results As of October 29, 2021, 54 patients with BBS enrolled the index trial, including 28 patients Conclusions Clinically beneficial effects of setmelanotide on body weight-related measures continued to be observed in patients with BBS for up to 2 years. Only 1 patient discontinued the LTE trial due to an adverse event, suggesting setmelanotide continued to have clinical benefit and was generally well tolerated. These data support the long-term use of setmelanotide in patients with BBS. Presentation: No date and time listed
Published: 2022

40. eP275: Quality of life in patients with Bardet-Biedl syndrome in a setmelanotide phase 3 trial

Author: Elizabeth Forsythe, Robert Haws, Jesus Argente, Philip Beales, Costel Chirila, Karine Clement, Hélène Dollfus, Gabriel Martos-Moreno, Ari Gnanasakthy, Brieana Buckley, Usha Mallya, and Andrea Haqq
Subjects: Genetics (clinical)
Published: 2022

41. 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

42. Severe phenotype in patients with large deletions of NF1

Author: Laurence, Pacot, Dominique, Vidaud, Audrey, Sabbagh, Ingrid, Laurendeau, Audrey, Briand-Suleau, Audrey, Coustier, Théodora, Maillard, Cécile, Barbance, Fanny, Morice-Picard, Sabine, Sigaudy, Olga O, Glazunova, Lena, Damaj, Valérie, Layet, Chloé, Quelin, Brigitte, Gilbert-Dussardier, Frédérique, Audic, Hélène, Dollfus, Anne-Marie, Guerrot, James, Lespinasse, Sophie, Julia, Marie-Christine, Vantyghem, Magali, Drouard, Marilyn, Lackmy, Bruno, Leheup, Yves, Alembik, Alexia, Lemaire, Patrick, Nitschké, Florence, Petit, Anne, Dieux Coeslier, Eugénie, Mutez, Alain, Taieb, Mélanie, Fradin, Yline, Capri, Hala, Nasser, Lyse, Ruaud, Benjamin, Dauriat, Sylvie, Bourthoumieu, David, Geneviève, Séverine, Audebert-Bellanger, Mathilde, Nizon, Radka, Stoeva, Geoffroy, Hickman, Gaël, Nicolas, Juliette, Mazereeuw-Hautier, Arnaud, Jannic, Salah, Ferkal, Béatrice, Parfait, Michel, Vidaud, Members Of The Nf France Network, Pierre, Wolkenstein, Eric, Pasmant, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cancer Research and Personalized Medicine - CARPEM [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 Necker - Enfants Malades [AP-HP], GHU AP-HP Centre Université de Paris, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), 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), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pontchaillou [Rennes], Groupe Hospitalier du Havre, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hôpital Sud [CHU Rennes], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Métropole Savoie [Chambéry], CHU Toulouse [Toulouse], Hôpital Purpan [Toulouse], Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital de Hautepierre [Strasbourg], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), CHU Limoges, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Le Mans (CH Le Mans), Hopital Saint-Louis [AP-HP] (AP-HP), Université de Rouen Normandie (UNIROUEN), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by grants by Association Neurofibromatoses et Recklinghausen Fondation CAP NF, Ligue Française Contre les Neurofibromatoses, INSERM (Nf1GeneModif project), and Ministère de l’Enseignement Supérieur et de la Recherche., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], 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)-CHU Necker - Enfants Malades [AP-HP], Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), 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), and Admin, Oskar
Subjects: Genotype-phenotype correlation, congenital, hereditary, and neonatal diseases and abnormalities, cardiovascular abnormalities, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, dysmorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, skeletal abnormalities, neurofibromatosis type 1, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, MPNSTs, learning disabilities, Neurofi-bromas, neoplasms, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, NF1 deletion, genotype–phenotype correlation, eye diseases, nervous system diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NF1, neurofibromas, NFs, malignant peripheral nerve sheath tumors, tumor predisposition
Abstract: Simple Summary Neurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Abstract Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.
Published: 2021

43. 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

44. Sleep-Disordered Breathing, Quality of Sleep and Chronotype in a Cohort of Adult Patients with Bardet-Biedl Syndrome

Author: Léa, Dormegny, Reana, Velizarova, Carmen M, Schroder, Ulker, Kilic-Huck, Henri, Comtet, Hélène, Dollfus, Patrice, Bourgin, and Elisabeth, Ruppert
Subjects: sleep disordered breathing, Bardet–Biedl syndrome, ciliopathy, chronotype, sleep apnea syndrome, circadian rhythm sleep wake disorder, Original Research
Abstract: Objective/Background Bardet–Biedl syndrome (BBS) is a rare but well-recognized ciliopathy with high genetic and phenotypic heterogeneity. Cardinal features include obesity, diabetes and high blood pressure (HBP), which are often associated with sleep-disordered breathing. Also, the high prevalence of blindness due to retinal dystrophy could affect circadian sleep–wake rhythms. We characterized in this cohort of adult BBS patients sleep-disordered breathing, sleep quality, daytime sleepiness and chronotype. Patients and Methods Thirty-two patients with genetically confirmed BBS were included in this observational single center study. Overnight respiratory polygraphy was performed for sleep apnea syndrome (SAS) in 30 patients. Quality of sleep, daytime sleepiness, fatigue and chronotype were assessed in 25 patients using Pittsburgh sleep quality index (PSQI), 14-day sleep diary (SD), Epworth sleepiness scale (ESS), Pichot fatigue scale (PFS) and Horne and Ostberg morningness-eveningness questionnaire (MEQ). Results Patients’ mean age was 32±11 years and mean BMI 32.6±7.7 kg/m2. Eleven (35%) patients had HBP and 7 (22%) diabetes. Moderate to severe sleep apnea syndrome (SAS) was present in 5 (17%) and was not associated with altered sleep, daytime sleepiness or fatigue. Most of the patients (63%) evaluated their sleep as of good quality (PSQI ≤ 5). Median scores of sleep quality, daytime sleepiness and fatigue were normal (PSQI of 3.0 [2.0–6.0], ESS of 9.0 [6.0–13.0] and PFS of 8.0 [3.0–13.0], respectively). Predominant chronotypes according to MEQ were either “intermediate” (57%) or “moderate morning” (29%). None had a free running sleep–wake cycle. 14-day SD revealed overall few awakenings at night and low daytime napping. Conclusions Given the cardiovascular risk factors, systematic screening for SAS should be considered in BBS patients, regardless of sleep and daytime vigilance complaints. None of these highly visually impaired patients had a circadian sleep–wake rhythm disorder. Further objective assessments are needed to better characterize sleep and circadian rhythms in BBS patients.
Published: 2021

45. 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

46. Author response for 'Periodontal (formerly type VIII ) Ehlers‐Danlos syndrome: description of 13 novel cases and expansion of the clinical phenotype'

Author: Anne Legrand, Xavier Jeunemaitre, Aymeric Courval, Elise Schaefer, Roland Jaussaud, Clarisse Billon, Agathe Chammas, Corinne Stoetzel, Marie-Cécile Manière, Sébastien Gaertner, Anthony Reyre, Agnès Bloch-Zupan, Dan Lipsker, Jean Muller, Salima El Chehadeh, Tiffany Busa, Laurence Bal, Hélène Dollfus, Catherine Petit, Karelle Benistan, Véronique Geoffroy, Salma Adham, and Anne-Claire Bursztejn
Subjects: medicine.medical_specialty, business.industry, Ehlers–Danlos syndrome, medicine, Type viii, Clinical phenotype, business, medicine.disease, Dermatology
Published: 2021

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

Author: Pierre Henry Gabrielle, Laurence Faivre, Isabelle Audo, Xavier Zanlonghi, Hélène Dollfus, A.A.H.J. (Alberta) Thiadens, Christina Zeitz, G.M.S. (Grazia) Verheijen - Mancini, Yaumara Perdomo, Saddek Mohand-Saïd, Eléonore Lizé, Vincent Lhussiez, Emeline F. Nandrot, Niyazi Acar, Catherine Creuzot-Garcher, José Alain Sahel, Muhammad Ansar, Christel Thauvin-Robinet, Laurence Duplomb, Romain Da Costa, Pierre Henry Gabrielle, Laurence Faivre, Isabelle Audo, Xavier Zanlonghi, Hélène Dollfus, A.A.H.J. (Alberta) Thiadens, Christina Zeitz, G.M.S. (Grazia) Verheijen - Mancini, Yaumara Perdomo, Saddek Mohand-Saïd, Eléonore Lizé, Vincent Lhussiez, Emeline F. Nandrot, Niyazi Acar, Catherine Creuzot-Garcher, José Alain Sahel, Muhammad Ansar, Christel Thauvin-Robinet, Laurence Duplomb, and Romain Da Costa
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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48. Author response for 'A <scp> BBS1 SVA </scp> F retrotransposon insertion is a frequent cause of <scp>Bardet‐Biedl</scp> syndrome'

Author: Sylvie Odent, Carmen C. Leitch, Michèle Mathieu-Dramard, Koenraad Devriendt, Clarisse Delvallée, Hélène Dollfus, Véronique Geoffroy, Erica E. Davis, Elsa Nourisson, Georgios Kellaris, Samuel Nicaise, Niklas Dahl, Corinne Stoetzel, Nicholas Katsanis, Jean-Francois Deleuze, Florence Demurger, Emmanuelle Génin, Manuela Antin, Joakim Klar, Richard Redon, Sophie Scheidecker, Christine Poitou-Bernert, J. L. Mandel, Anne-Sophie Leuvrey, Boris Keren, Jean Muller, and Christel Depienne
Subjects: Genetics, Bardet–Biedl syndrome, BBS1, business.industry, Medicine, Retrotransposon, business, medicine.disease
Published: 2020

49. 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

50. Relative adipose tissue failure in Alström syndrome drives obesity-induced insulin resistance

Author: Vincent Marion, Nikolai Petrovsky, Hélène Dollfus, Richard P Steeds, Jeremy W Tomlinson, Karine Clement, Pierre Bel Lassen, Nadia Messaddeq, Konstantinos Manolopoulos, Charlotte Dawson, Dorothée Girard, Cathy Obringer, Shanat Baig, Tarekegn Geberhiwot, and Ada Admin
Abstract: Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (Almsflin/flin;Adipo-Cre+/-) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.
Published: 2020

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