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Eur J Hum Genet. 2017 Feb;25(2):183-191. doi: 10.1038/ejhg.2016.165. Epub 2016 Nov 30.

Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition.

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Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Germany.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Centre de Référence Anomalies du Développement et Syndromes Malformatifs PACA, Service de génétique Clinique, Hôpital Timone Enfants, Marseille, France.
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.
Laboratoire de Génétique Moléculaire, CHU de Dijon, Dijon, France.
Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
Zentrum für Humangenetik, Universitätsklinikum Regensburg, Regensburg, Germany.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.


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.

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