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  • Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature

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Phenotypes
Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature
  1. M Balasubramanian1,
  2. J Willoughby2,
  3. A E Fry3,4,
  4. A Weber5,
  5. H V Firth6,
  6. C Deshpande7,
  7. J N Berg8,
  8. K Chandler9,10,
  9. K A Metcalfe9,10,
  10. W Lam11,
  11. D T Pilz12,
  12. S Tomkins13,
  13. DDD Study14
  1. 1 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
  2. 2 Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
  3. 3 Institute of Medial Genetics, University Hospital of Wales, Cardiff, UK
  4. 4 Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
  5. 5 Clinical Genetics Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
  6. 6 East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK
  7. 7 Department of Clinical Genetics, Guy's & St. Thomas’ Hospital NHS Trust, London, UK
  8. 8 Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  9. 9 Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK
  10. 10 Division of Evolution and Genomic sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  11. 11 Clinical Genetics Unit, Western General Hospital, Edinburgh, UK
  12. 12 West of Scotland Genetics Service, Glasgow, UK
  13. 13 Clinical Genetics Service, University Hospitals of Bristol NHS Foundation Trust, Bristol, UK
  14. 14 DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  1. * Correspondence to
    Dr Meena Balasubramanian, Sheffield Clinical Genetics Service, Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK; meena.balasubramanian{at}nhs.net

Abstract

Background Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients.

Objectives Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study.

Methods Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study.

Results By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. 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.

Discussion 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.

Conclusions 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.

  • ASXL3, intellectual disability, Marfanoid habitus, heterozygous, loss-of-function
  • Developmental
  • Molecular genetics
  • Clinical genetics

https://doi.org/10.1136/jmedgenet-2016-104360

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    Footnotes

    • MB and JW are joint first authors.

    • Correction Notice This article has been corrected since it published online first. The photograph of patient 5 has been updated in Figure 1 and Figure 3E. Edits have been made to some of the data in table 1 and the 'Intellectual disability' section has been edited to accurately reflect the number of patients attending a special school (10/12) and the degree of ID in the patients. Figure legend for Figure 3 has been added ‘Frontal and profile images of patients with ASXL3 variants at varying ages’. K Chandler affiliation is 9,10. D T Pilz middle initial has been updated. The number for hypotonia has been updated in the abstract results (11/12). In Table 1, edits have been made as follows for Patient 3: column: weight 25th centile and ‘No’ for hypotonia with R/V across for ‘Hypotonia’ reading 11/12.

    • Contributors All authors recruited their respective patients to the DDD study and provided data regarding their patients; DDD study provided trio exome sequencing data. MB and JB planned the study; MB recruited Patient 1 to DDD and wrote the manuscript; all authors reviewed and contributed to the manuscript.

    • Funding The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Cambridge South REC.

    • Provenance and peer review Not commissioned; externally peer reviewed.