Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients withde novo, heterozygous, loss-of-function mutations inASXL3and review of published literature

Abstract

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.

The phenotypic spectrum of Xia‐Gibbs syndrome

“…Alternatively, the absence of pathogenic missense variants may simply reflect the early period of discovery and reduced ascertainment due to a potentially milder phenotype. A similar, illustrative example is Bainbridge‐Ropers Syndrome (BRS: OMIM #615485), where severe phenotypes resulting from de novo truncating mutations in four cases led to the initial disease gene identification of ASXL3 (Bainbridge et al, ) and follow up discovery of additional truncating mutations (Balasubramanian et al, ). Recently, however, compound missense heterozygous alleles in ASXL3 have been suggested to cause a mild form of BRS in one patient (Giri et al, ) and by analogy, future observation of missense mutations in AHDC1 leading to pathogenicity cannot be discounted.…”

Whole exome sequencing diagnoses the first fetal case of Bainbridge‐Ropers syndrome presenting as pontocerebellar hypoplasia type 1

“…BRPS was first described in 2013, in four patients with ASXL3 de novo mutations (Bainbridge et al, ). To date 29 patients aged 4 months to 22 years were reported (Bainbridge et al, ; Balasubramanian et al, ; Contreras‐Capetillo et al, ; Dinwiddie et al, ; Hori et al, ; Kuechler et al, ; Srivastava et al, ; Zhu et al, ). Clinical features of reported cases and our fetal case are summarized in Table .…”

“…Bainbridge‐Ropers Syndrome (BRPS: OMIM 615485) is a recently identified severe developmental disorder characterized by failure to thrive, severe developmental delay, feeding problems, and facial dysmorphism caused by de novo dominant truncating mutation in the additional sex combs‐like 3 ( ASXL3 ) gene (Bainbridge et al, ). About twenty BRPS cases have been reported to date (Bainbridge et al, ; Balasubramanian et al, ; Contreras‐Capetillo, Vilchis‐Zapata, Ribbón‐Conde, & Pinto‐Escalante, ; Dinwiddie et al, ; Hori et al, ; Kuechler et al, ; Srivastava et al, ; Zhu et al, ), but no fetal case has been described. Interestingly, de novo mutations in another gene family member, ASXL1 , cause Bohring‐Opitz syndrome (OMIM 605039), which shares some clinical features with BRPS.…”

Mild prominence of the Sylvian fissure in a Bainbridge‐Ropers syndrome patient with a novel frameshift variant in ASXL3

“…BRPS is caused by de novo dominant truncating variants in the Transcriptional Regulator gene Additional Sex Combs Like 3 (ASXL3), while missense variants in ASXL3 have been identified in individuals with autism spectrum disorder (ASD) [1,3,5,14]. ASXL family members are assumed to be epigenetic regulators that are involved in hereditary neurological disorders as well as malignancies [1,2,6,8].…”