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1. TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility

Author

Aafke Engwerda, Maarten P. van den Berg, Wilhelmina S. Kerstjens-Frederikse, Yvonne J. Vos, Bert B.A. de Vries, Tuula Rinne, Marc T R Roofthooft, Paulien A Terhal, Patrick Deelen, Conny M. A. van Ravenswaaij-Arts, Barbara Frentz, Katharina Löhner, Trijnie Dijkhuizen, Erika Leenders, Cardiovascular Centre (CVC), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Joint Instability, CONGENITAL HEART-DEFECTS, Pathology, medicine.medical_specialty, TAK1, Heart Valve Diseases, Cardiomyopathy, GROWTH FAILURE, Dwarfism, Disease, Short stature, Article, Mitral valve, Genetics, medicine, Humans, MICRODELETION, DYSPLASIA, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, business.industry, Syndrome, medicine.disease, Phenotype, DELINEATION, medicine.anatomical_structure, Mitral Valve, Noonan syndrome, Chromosomes, Human, Pair 6, medicine.symptom, Cardiomyopathies, Haploinsufficiency, business, Gene Deletion
Abstract

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".

Published
2021
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2. Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications

Author

Gioia Mastromoro, Alma Kuechler, Francesca Clementina Radio, Yoann Vial, Elena Andreucci, Tuula Rinne, Erika Leenders, Kara Ranguin, Emanuela Scarano, Marine Legendre, Marion Gérard, Julia Brinkmann, Alessandro De Luca, Paola Daniele, Kerstin Kutsche, Francesca Pantaleoni, Ineke van der Burgt, Christina Lissewski, Maria Cristina Digilio, Hélène Cavé, Yline Capri, Valérie Chune, Francesca Romana Lepri, Martin Zenker, Marco Tartaglia, Laura Mazzanti, Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Radboud University Medical Center [Nijmegen], St. Orsola University Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Institut für Humangenetik, Universitätsklinikum Essen, Essen, Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Pellegrin, CHU de Bordeaux, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Anna Meyer Children's Hospital Florence, University of Florence, and Department of Experimental Medicine, Sapienza University of Rome (Italy)

Subjects
Adult, Male, Adolescent, Medizin, Bioinformatics, Short stature, Article, Mapk signaling pathway, Lymphatic System, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Genotype, Genetics, Humans, Medicine, In patient, Child, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Protein function, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Noonan Syndrome, 030305 genetics & heredity, Infant, medicine.disease, Phenotype, 3. Good health, Lymphatic system, Child, Preschool, Son of Sevenless Proteins, Mutation, Noonan syndrome, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.

Published
2020
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3. Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

Author

Erika Leenders, Lotte Kleimeier, Jos M. T. Draaisma, Willemijn M. Klein, and Julia Sleutjes

Subjects
musculoskeletal diseases, Pathology, medicine.medical_specialty, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Review Article, medicine.disease, Lymphatic abnormality, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Genetics, medicine, Noonan syndrome, business, Genetics (clinical)
Abstract

Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic PTPN11 variants to 38% in patients with pathogenic RIT1 variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic SOS1 to 29% in patients with pathogenic RIT1 variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic PTPN11 variants to 44% in patients with pathogenic SOS1 variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic RIT1 variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.

Published
2022

4. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Ian R. Berry, Martin R. Larsen, Ann M. Neumeyer, Lilian Bomme Ousager, Leah J. Rowe, Richard E. Person, Chanika Phornphutkul, David A. Koolen, Constance T. R. M. Stumpel, Konrad Platzer, Elizabeth J. Bhoj, Eric Chater-Diehl, Jason Bunn, Erika Leenders, Koen L.I. van Gassen, Joshua Charkow, Rosanna Weksberg, Ny Hoang, Roos Cuperus, Davor Lessel, Rolph Pfundt, Oana Caluseriu, Sarah J. Goodman, Leandra Folk, Fanggeng Zou, Michelle T. Siu, David Chitayat, Dmitrijs Rots, Jeroen R. Vermeulen, Shuxi Liu, Cheryl Cytrynbaum, Elin Tønne, Hein Brackel, Mareike Mertens, Jennifer Campbell, Jonathan B. Strober, Maja Hempel, Tjitske Kleefstra, Małgorzata J.M. Nowaczyk, Amy Crunk, Marta Pacio-Míguez, Fernando Santos-Simarro, Nicola Brunetti-Pierri, Christa de Geus, María Palomares-Bralo, Lisenka E.L.M. Vissers, Sander Pajusalu, Peter Kannu, Sanaa Choufani, Kristin Lindstrom, Margarita Saenz, Berkley Schmidt, Daniëlle G.M. Bosch, Han G. Brunner, Arie van Haeringen, Ellen van Binsbergen, Brianna Pruniski, Claudia A. L. Ruivenkamp, William G. Wilson, Servi J. C. Stevens, Susan Walker, Kristian Tveten, Zain Awamleh, Gerarda Cappuccio, Alexander J. M. Dingemans, Michael Kwint, Ebba Alkhunaizi, Jonas Denecke, Alyssa Ritter, Eric W. Klee, Bert B.A. de Vries, Jeske V.T. van Harssel, Stephen Meyn, A. Chantal Deden, Francisca Millan, Eva Morava, Ingrid M. Wentzensen, Anne Slavotinek, Stephen W. Scherer, Katrin Õunap, Tuula Rinne, Jessica A. Radley, Yili Xie, Thatjana Gardeitchik, Laura Schultz-Rogers, Karit Reinson, Ronald D. Cohn, Hui Yang, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA Klinische Genetica (5), Rots, Dmitrij, Chater-Diehl, Eric, Dingemans, Alexander J M, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert B A, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance T R M, Stevens, Servi J C, Vermeulen, Jeroen R, van Harssel, Jeske V T, Bosch, Danielle G M, van Gassen, Koen L I, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jona, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roo, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata J M, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka E L M, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna

Subjects
0301 basic medicine, Heart Septal Defects, Ventricular, Male, DNA methylation signature, nonsense-mediated decay, speech delay, PROTEIN, 030105 genetics & heredity, PHENOTYPE, epigenomic, Medical and Health Sciences, Epigenesis, Genetic, Craniofacial Abnormalities, Cohort Studies, Neurodevelopmental disorder, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Growth Disorders, Epigenomics, non-FLHS SRCAP-related NDD, Genetics, Adenosine Triphosphatases, Genetics & Heredity, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SOTOS-LIKE, Biological Sciences, SRCAP, Hypotonia, AT-HOOK, 3. Good health, Phenotype, Mental Health, intellectual disability, Speech delay, DNA methylation, Female, medicine.symptom, Abnormalities, Multiple, EXON 34, Intellectual and Developmental Disabilities (IDD), Locus (genetics), Biology, genotype-phenotype correlation, DIAGNOSIS, Article, 03 medical and health sciences, Genetic, Clinical Research, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Floating-Harbor syndrome, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, Heart Septal Defects, Infant, Newborn, Ventricular, dNaM, Infant, DNA Methylation, medicine.disease, Newborn, neurodevelopmental disorder, GENE, Brain Disorders, 030104 developmental biology, Floating–Harbor syndrome, Case-Control Studies, Mutation, epigenomics, EPISIGNATURES, Epigenesis
Abstract

Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021
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5. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Bertrand Isidor, Ruth Armstrong, Thabo M. Yates, Susan M. White, Ruth Richardson, Solveig Heide, Katherine B. Burke, Tjitske Kleefstra, Marie Vincent, Meena Balasubramanian, Maria Irene Valenzuela Palafoll, Sébastien Küry, Rolph Pfundt, Ruth Newbury-Ecob, Sahar Mansour, Wendy K. Chung, Caroline Nava, Sofia Douzgou, Erika Leenders, Annachiara De Sandre-Giovannoli, Saba Sharif, Andrew E. Fry, Helen Stewart, Nicola K. Ragge, Alexander J. M. Dingemans, Pradeep C. Vasudevan, Alison Foster, Sahar Elouej, Shadi Albaba, François-Guillaume Debray, Boris Keren, Serwet Demirdas, Francis H. Sansbury, Thomas Scheffner, Arie van Haeringen, Alice S. Brooks, Meyke Schouten, Helen Cox, Kate Wilson, Sheffield Children's NHS Foundation Trust, University of Sheffield [Sheffield], Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Birmingham Children’s Hospital, Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], Addenbrooke's Hospital, Cambridge University NHS Trust, University Hospital of Wales, Oxford Brookes University, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), 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)-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), St. George’s Hospital University, Oxford University Hospitals NHS Foundation Trust, Partenaires INRAE, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Leiden University Medical Center (LUMC), Reutlingen University, Centre Hospitalier Universitaire de Liège (CHU-Liège), Murdoch Children's Research Institute (MCRI), University of Melbourne, Vall d'Hebron University Hospital [Barcelona], University Hospitals Bristol, Clinical Genetics, Institut Català de la Salut, [Balasubramanian M] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK. [Dingemans AJM] Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. [Albaba S] Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Richardson R] Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK. [Yates TM] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Cox H] West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK. [Palafoll MIV] Servei de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University Hospital of Wales (UHW), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Universiteit Leiden

Subjects
Male, Pediatrics, Genetic testing, Developmental Disabilities, Craniofacial Abnormalities, Intellectual disability, Missense mutation, Child, Genetics (clinical), trastornos mentales::trastornos del desarrollo neurológico::discapacidades del desarrollo [PSIQUIATRÍA Y PSICOLOGÍA], 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 030305 genetics & heredity, Cognition, Syndrome, Autism spectrum disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Fenotip, Sin3 Histone Deacetylase and Corepressor Complex, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Trastorns del desenvolupament - Aspectes genètics, Infants, medicine.medical_specialty, Adolescent, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, Mental Disorders::Neurodevelopmental Disorders::Developmental Disabilities [PSYCHIATRY AND PSYCHOLOGY], Intellectual Disability, Genetics, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Attention deficit hyperactivity disorder, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Autism, business, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS]
Abstract

Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation

Published
2021
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6. De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

Author

Charu Deshpande, Joke B. G. M. Verheij, H Van Bokhoven, Siddharth Banka, J. S. Klein Wassink-Ruiter, Elizabeth J. Bhoj, S. C. Huffels, R. Pfundt, Ernie M.H.F. Bongers, Anne Gregor, A.P.M. de Brouwer, André Reis, Christiane Zweier, Hakon Hakonarson, Nicola K. Ragge, L. Gompertz, Dong Li, Sanmati Cuddapah, Alexander P.A. Stegmann, Sally Ann Lynch, A.T. Vulto-van Silfhout, Willie Reardon, Gyri Aasland Gradek, Daniel L. Polla, Kate Chandler, C. T. R. M. Stumpel, B. B. A. de Vries, R. Wennekes, Elaine H. Zackai, Siren Berland, Erika Leenders, K. Hill-Karfe, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
0301 basic medicine, FG syndrome, Mutation, Missense, 030105 genetics & heredity, Biology, Short stature, MED12, 03 medical and health sciences, Exon, BLEPHAROPHIMOSIS, Genes, X-Linked, Intellectual Disability, medicine, Missense mutation, Humans, Genetics(clinical), TRANSCRIPTION, Gene, MUTATION, Genetics (clinical), Genetics, OHDO SYNDROME, Mediator Complex, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Syndrome, medicine.disease, Phenotype, Blepharophimosis, GENE, DELINEATION, FG SYNDROME, 030104 developmental biology, Neurodevelopmental Disorders, Mental Retardation, X-Linked, Female, medicine.symptom, MENTAL-RETARDATION
Abstract

Contains fulltext : 234992.pdf (Publisher’s version ) (Closed access) PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Published
2021
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7. Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD)

Author

Christian P. Kratz, Jan Loeffen, Erika Leenders, Nicoline Hoogerbrugge, John Burn, Roger J. M. Brüggemann, Harm Westdorp, Marjolijn C.J. Jongmans, and Pediatrics

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Colorectal cancer, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Review Article, MLH1, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Neoplastic Syndromes, Hereditary, Internal medicine, Neoplasms, Genetics, medicine, PMS2, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Humans, Child, neoplasms, Genetics (clinical), Germ-Line Mutation, Mismatch Repair Endonuclease PMS2, Cancer prevention, Aspirin, business.industry, Brain Neoplasms, Cancer, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, digestive system diseases, MSH6, DNA-Binding Proteins, 030104 developmental biology, MutS Homolog 2 Protein, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], MSH2, 030220 oncology & carcinogenesis, business, Colorectal Neoplasms, MutL Protein Homolog 1, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Item does not contain fulltext Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

Published
2018

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