RT Journal Article
SR Electronic
T1 Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with <em>de novo</em>, heterozygous, loss-of-function mutations in <em>ASXL3</em> and review of published literature
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2016-104360
DO 10.1136/jmedgenet-2016-104360
A1 M Balasubramanian
A1 J Willoughby
A1 A E Fry
A1 A Weber
A1 H V Firth
A1 C Deshpande
A1 J N Berg
A1 K Chandler
A1 K A Metcalfe
A1 W Lam
A1 D Pilz
A1 S Tomkins
A1 DDD Study
YR 2017
UL http://jmg.bmj.com/content/early/2017/01/18/jmedgenet-2016-104360.abstract
AB 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 (12/12), 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 (12/12) and significant feeding difficulties (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.