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2 results on '"CAUSE GENITOPATELLAR SYNDROME"'

1. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Author

Yan, K.Z., Rousseau, J., Littlejohn, R.O., Kiss, C., Lehman, A., Rosenfeld, J.A., Stumpel, C.T.R., Stegmann, A.P.A., Robak, L., Scaglia, F., Nguyen, T.T.M., Fu, H., Ajeawung, N.F., Camurri, M.V., Li, L., Gardham, A., Panis, B., Almannai, M., Sacoto, M.J.G., Baskin, B., Ruivenkamp, C., Xia, F., Bi, W., Cho, M.T., Potjer, T.P., Santen, G.W.E., Parker, M.J., Canham, N., McKinnon, M., Potocki, L., MacKenzie, J.J., Roeder, E.R., Campeau, P.M., Yang, X.J., DDD Study, CAUSES Study, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
0301 basic medicine, Male, Developmental Disabilities, PZP DOMAIN, HBO1 ACETYLTRANSFERASE, Histones, Mice, Intellectual disability, Global developmental delay, Child, Genetics (clinical), Histone Acetyltransferases, Genetics, Mice, Knockout, ZINC-FINGER PROTEIN, Nuclear Proteins, Acetylation, Syndrome, Chromatin, DNA-Binding Proteins, Histone, Muscle Hypotonia, Female, EXPRESSION, Adolescent, Biology, KAT6B, Article, 03 medical and health sciences, Histone H3, Intellectual Disability, medicine, Animals, Humans, HEMATOPOIETIC STEM-CELLS, Epigenetics, Histone H3 acetylation, Alleles, Adaptor Proteins, Signal Transducing, CAUSE GENITOPATELLAR SYNDROME, Lysine, PHD FINGER, medicine.disease, Bromodomain, Mice, Inbred C57BL, 030104 developmental biology, DE-NOVO MUTATIONS, Face, Mutation, biology.protein, Carrier Proteins, CAENORHABDITIS-ELEGANS
Abstract

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Syrhptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.

Published
2017
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2. Further delineation of the KAT6B molecular and phenotypic spectrum

Author

DDD study, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan FM, Smith, Janine, Clayton-Smith, Jill, Regional Genetic Service, St Mary's Hospital, Manchester, Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Haukeland University Hospital, Royal Brsibane and Womens' Hospital, The University of Queensland, Department of Clinical Genetics, Children’s Hospital at Westmead, Service de génétique médicale, AP-HP Hôpital Necker - Enfants Malades [Paris], Institute of Human Genetics, Universität Ulm, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Karolinska University Hospital, Karolinska University Hospital [Stockholm], University Hospitals Bristol, University of Birmingham [Birmingham], Hacettepe University Children's Hospital, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Division of Genetics, Birth Defects and Metabolism, Children's hospital of Chicago, Clinical Genetics, Guy's Hospital [London], North West london hospitals NHS Trust, Department of Clinical Genetics, Northampton General Hospital, Northampton, Barzilai Medical Center, Cliniques Universitaires St Luc, Université Catholique de Louvain (UCL), Service de génétique [Tours], Hôpital Bretonneau - CHRU Tours, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1) - Centre National de la Recherche Scientifique (CNRS) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1) - CHU Pontchaillou [Rennes] - Hôpital Sud, Pediatrics, Istanbul University Cerrahpasa, Birmingham Women’s Hospital, University of Groningen [Groningen], Belfast City Hospital, Centre For Medical Genetics, Clinical Genetic Service, Department of Health, Institute of Medical Genetics, Heath Park, Cardiff, National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Dipartimento di Medicina Molecolare, University of Pavia, UZ Leuven - campus Gasthuisberg, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children’s Hospital, Service de Génétique, CHU Reims - Hôpital Maison Blanche - IFR 53, Leiden University Medical Center, Service de Génétique humaine, Université de Lausanne (UNIL), Çocuk Sağlığı ve Hastalıkları, University of Bergen (UiB), Westmead Hospital [Sydney], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Sheffield Children's NHS Foundation Trust, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Leiden University Medical Center (LUMC), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Nottingham University Hospitals NHS Trust (NUH), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Università degli Studi di Pavia = University of Pavia (UNIPV), Universiteit Leiden-Universiteit Leiden, Université de Lausanne = University of Lausanne (UNIL), DDD study, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, DNA Mutational Analysis, Medizin, Gene Expression, Kidney, Severity of Illness Index, Craniofacial Abnormalities, Missense mutation, Exome, Genetics (clinical), Histone Acetyltransferases, Genetics, OHDO SYNDROME, Patella, Exons, Hypotonia, 3. Good health, Blepharophimosis/diagnosis, Blepharophimosis/genetics, Child, Preschool, Congenital Hypothyroidism/diagnosis, Congenital Hypothyroidism/genetics, Craniofacial Abnormalities/diagnosis, Craniofacial Abnormalities/genetics, Diagnosis, Differential, Facies, Female, Genetic Association Studies, Genotype, Heart Defects, Congenital/diagnosis, Heart Defects, Congenital/genetics, Histone Acetyltransferases/genetics, Humans, Intellectual Disability/diagnosis, Intellectual Disability/genetics, Joint Instability/diagnosis, Joint Instability/genetics, Kidney/abnormalities, Kidney/pathology, Mutation, Patella/abnormalities, Patella/pathology, Phenotype, Psychomotor Disorders/diagnosis, Psychomotor Disorders/genetics, Scrotum/abnormalities, Scrotum/pathology, Urogenital Abnormalities/diagnosis, Urogenital Abnormalities/genetics, Scrotum, Medical genetics, genitopatellar, Say-Barber-Biesecker, medicine.symptom, Psychomotor disorder, Haploinsufficiency, Heart Defects, Congenital, Joint Instability, medicine.medical_specialty, Biology, Blepharophimosis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, KAT6B, Article, Intellectual Disability, medicine, Congenital Hypothyroidism, CAUSE GENITOPATELLAR SYNDROME, medicine.disease, blepharophimosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Urogenital Abnormalities, Genitopatellar syndrome, HISTONE ACETYLTRANSFERASE KAT6B, Psychomotor Disorders, MENTAL-RETARDATION
Abstract

International audience; KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Published
2015
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