Speech and Language Development of Two Brothers With Bainbridge-Ropers Syndrome: Phenotypic and Bioinformatic Support for a Cerebellar ASXL3 Hypothesis.

Abstract

Bainbridge-Ropers syndrome (BRPS) is a rare neurodevelopmental disorder caused by variants in the ASXL3 gene. Nearly all cases are de novo, representing widely varying ASXL3 genotypes. Commonly observed traits include feeding difficulties, global motor delays, hypotonia, intellectual disability, autism, seizures, and craniofacial and skeletal changes. Difficulty with verbal communication is present in all cases, yet speech and language characteristics have not been described closely. Here, we present two brothers with BRPS due to suspected parental germline mosaicism. Clinical histories were based on chart review, interviews with a parent, and direct observations. Despite identical genotypes, phenotypic expression varies in severity. Both children have developmental coordination disorder, consistent with cerebellar dysfunction. Child 1, age 11 years, has childhood apraxia of speech (CAS) and largely intact cognitive skills. He received specialized therapy focused on motor learning and communicates verbally. Child 2, age 8, has oral apraxia, intellectual disability, autism, and language disorder. He communicates using non-speaking means. Bioinformatic analyses show that ASXL3 belongs to a regulatory network with highest cerebellar expression up to postconception Week 24. This study contributes speech and language descriptions, illustrates phenotypic variability likely resulting from the transcriptional regulatory network interacting with environmental influences, and underscores the importance of therapies that take motor discoordination into account.