title: Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients withde novo, heterozygous, loss-of-function mutations inASXL3and review of published literature.
abstract: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused byde novotruncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients.
  
  
  
  Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study.
  
  
  
  Trio-based exome sequencing was performed on all 12 patients included in this study, which found ade novotruncating mutation inASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study.
  
  
  
  By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region withinASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young.
  
  
  
  Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance.
  
  
  
  This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore.
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: M
authors.identifier: 0000-0003-1488-3695
authors.initials: M
authors.lastname: Balasubramanian
authors.affiliation: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: J
authors.initials: J
authors.lastname: Willoughby
authors.affiliation: Institute of Medial Genetics, University Hospital of Wales, Cardiff, UK.|Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Fry
authors.affiliation: Clinical Genetics Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Weber
authors.affiliation: East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: H V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Department of Clinical Genetics, Guy's & St. Thomas' Hospital NHS Trust, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: J N
authors.initials: JN
authors.lastname: Berg
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.|Division of Evolution and Genomic sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Chandler
authors.affiliation: Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.|Division of Evolution and Genomic sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: K A
authors.initials: KA
authors.lastname: Metcalfe
authors.affiliation: Clinical Genetics Unit, Western General Hospital, Edinburgh, UK.
authors.forename: W
authors.initials: W
authors.lastname: Lam
authors.affiliation: West of Scotland Genetics Service, Glasgow, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Pilz
authors.affiliation: Clinical Genetics Service, University Hospitals of Bristol NHS Foundation Trust, Bristol, UK.
authors.forename: S
authors.initials: S
authors.lastname: Tomkins
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D000073658:Loss of Function Mutation / Q000235:genetics*; D008297:Male; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*; D000073359:Exome Sequencing; D055815:Young Adult; D012097:Repressor Proteins
chemical_list: D014157:Transcription Factors; C494423:ASXL3 protein, human; D012097:Repressor Proteins
keywords: ASXL3, intellectual disability, Marfanoid habitus, heterozygous, loss-of-function; Clinical genetics; Developmental; Molecular genetics