Bainbridge-Ropers Syndrome

A number sign (#) is used with this entry because Bainbridge-Ropers syndrome (BRPS) is caused by heterozygous mutation in the ASXL3 gene (615115) on chromosome 18q12.

Description

Bainbridge-Ropers syndrome (BRPS) is a developmental disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, hypotonia, feeding difficulties, poor growth, and dysmorphic facial features (summary by Srivastava et al., 2016).

Clinical Features

Bainbridge et al. (2013) reported 4 individuals from 4 unrelated families with phenotypic features similar to those of Bohring-Opitz syndrome (605039) but with no specific recognizable syndromic diagnosis. Three of the subjects had similar clinical histories, including severe psychomotor retardation, feeding problems, severe postnatal growth retardation, arched eyebrows, anteverted nares, and ulnar deviation of the hands. The fourth subject also had anteverted nares but had less severe psychomotor retardation and normal growth. No patient had the typical 'BOS posture' of elbow and wrist flexion, or of myopia or trigonocephaly. Only 1 subject had brain MRI, which showed global mild white matter volume loss, secondary brainstem hypoplasia, and bilateral hypoplasia/dysplasia of cerebellar tonsils. MR spectroscopy was normal.

Srivastava et al. (2016) reported 3 unrelated patients with BRPS. All had feeding difficulties necessitating a feeding tube, failure to thrive, hypotonia, and developmental delay with absent speech and poor or absent independent walking. They had variable dysmorphic features, including arched eyebrows, downslanting palpebral fissures, broad nasal bridge with short nose and anteverted nares, low-set ears, and small chin. Brain imaging, performed in 2 patients, showed loss of white matter; 1 patient had a thin corpus callosum.

Balasubramanian et al. (2017) reported 12 unrelated patients with BRPS confirmed by genetic analysis. The patients, who ranged in age from 4 to 22 years, were ascertained from the Deciphering Developmental Disorders (DDD) project. Most patients presented in early infancy with feeding difficulties, poor overall growth, relative microcephaly, and hypotonia. All had delayed psychomotor development with moderate to profound intellectual disability and delayed walking. Two patients were nonambulatory and 9 were nonverbal. Most also had autistic features and 11 were in a special needs school. Three patients had controlled seizures and several had sleep problems. The patients had common, if variable, dysmorphic features, including prominent forehead, narrow head, hypertelorism, down- or upslanting palpebral fissures, strabismus, high-arched eyebrows, long tubular nose, prominent nasal bridge, broad or bulbous nasal tip, low columella, open mouth with everted lower lip, high-arched palate, and crowded teeth. Three patients had a marfanoid habitus with arachnodactyly, tall stature, pes planus, and scoliosis. A few patients had nonspecific minor abnormalities on brain imaging.

Molecular Genetics

Using whole-exome and whole-genome sequencing, Bainbridge et al. (2013) identified different de novo nonsense and frameshift mutations in the ASXL3 gene in each of the 4 patients (615115.0001-615115.0004).

In 3 unrelated patients with BRPS, Srivastava et al. (2016) identified 3 de novo heterozygous frameshift or nonsense mutations in the ASXL1 gene (615115.0005-615115.0007). Fibroblasts derived from 1 of the patients with a frameshift mutation in the 5-prime cluster region (c.1448dupT; 615115.0005) showed about a 50% decrease in ASXL1 mRNA and protein levels, consistent with haploinsufficiency. These cells showed significantly increased levels of H2AK119Ub1, indicating that this mutation disrupts the normal activity of the polycomb repressive deubiquitination (PR-DUB) complex, which functions to remove the monoubiquitin from lysine-119 of histone H2A (H2AK119Ub1), thus playing a role in chromatin remodeling and transcriptional regulation. Transcriptome analysis of these cells showed dysregulation of many genes, including those involved in transcriptional regulation, development, and proliferation, as well as in digestive tract development. These findings highlighted a role for dynamic regulation of H2A ubiquitination in development and disease.

In 12 unrelated patients with BRPS, Balasubramanian et al. (2017) identified 12 different de novo heterozygous nonsense or frameshift mutations in the ASXL3 gene (see, e.g., 615115.0006 and 615115.0008). The patients were ascertained from the Deciphering Developmental Disorders (DDD) project, and the mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but all were predicted to result in a loss of function. The authors noted that the mutations reported by Bainbridge et al. (2013) clustered mainly within the 5-prime end of exon 11 between codons 404 and 659. This region lies between the N-terminal protein scaffolding functional domains of the gene and the C-terminal chromatin/DNA-targeting functional domain. Among their cohort, Balasubramanian et al. (2017) noted that 5 of the identified mutations occurred within the original cluster region, whereas 7 occurred 3-prime to this region, suggesting a second cluster region between codons 1045 and 1444. There were no phenotypic differences between patients with mutations in the different cluster regions.