title: Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition.
abstract: Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Johanna Christina
authors.initials: JC
authors.lastname: Czeschik
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hüffmeier
authors.affiliation: Centre de Référence Anomalies du Développement et Syndromes Malformatifs PACA, Service de génétique Clinique, Hôpital Timone Enfants, Marseille, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Busa
authors.affiliation: Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Beck-Woedl
authors.affiliation: Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, Hôpital d'Enfants, Dijon, France.|EA 4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Laboratoire de Génétique Moléculaire, CHU de Dijon, Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bader
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Zentrum für Humangenetik, Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Olaf
authors.initials: O
authors.lastname: Rittinger
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005183:Failure to Thrive / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D012097:Repressor Proteins
chemical_list: D014157:Transcription Factors; C494423:ASXL3 protein, human; D012097:Repressor Proteins