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.

Limited studies have been conducted on pubertal development in populations with pre-existing medical conditions. More than 20-fold increased risk of early puberty has been reported in neurodevelopmental disorders; however, this is a heterogeneous group. There have been limited past studies examining the timing, duration, or characteristics of pubertal or menstrual cycle development in patients with ASXL-related disorders. This study aimed to gather empirical cross-sectional parent survey data regarding pubertal development in adolescents diagnosed with Bohring-Opitz syndrome (BOS) (ASXL1), Shashi-Pena syndrome (SPS) (ASXL2), or Bainbridge-Ropers syndrome (BRS) (ASXL3). Our findings showed evidence for parental and perceived provider concern for premature pubarche and possible precocious puberty (PP) in BOS (ASXL1) males and females. Findings between the BOS (ASXL1) and BRS (ASXL3) individuals differed, representing distinct pubertal phenotypes within these populations. Notable trends toward premature development may warrant a low threshold for pediatric endocrinological evaluation in this population. The characterization and description of a pubertal profile for the ASXL-related syndromes can help inform providers and parents when navigating this stage of development. Our study findings also highlight the need for prospective natural history studies to further define the contribution of pubertal development to the ASXL disorders phenotypes.

Bainbridge-Ropers syndrome (BRPS, OMIM #615485) is a rare, heterogeneous autosomal dominant genetic disease that is mainly characterized by intellectual disability (ID) of varying degrees, developmental delay (DD), language impairments, failure to thrive, behavioral issues, hypotonia, feeding difficulties, and distinctive craniofacial features. It is caused by heterozygous pathogenic variants in the additional sex combs-like 3 (ASXL3, OMIM #615115) gene. In this study, four Chinese patients were diagnosed with BRPS caused by ASXL3 variants through whole exome sequencing. We detected two novel and two previously reported variants of the ASXL3 gene (NM_030632.3) in these 4 unrelated Chinese patients: two novel variants, namely, c.1276del (p.Val426*) and c.3750del (p.Glu1251Asnfs*5), and two recurrent variants, namely, c.4330C>T (p.Arg1444*) and c.4336_4337delAG (p.Arg1446fs*2). All four patients had a clinical profile similar to that associated with BRPS. Compared with previously reported cases of BRPS, these patients exhibited novel complications, including long eyelashes, congenital laryngeal cartilage hypoplasia and dextrocardia. These findings broaden our understanding of the mutational and clinical spectrum of BRPS, emphasizing the importance of long-term monitoring and vigilance regarding potential complications, such as cardiac abnormalities, in BRPS patients.

Bainbridge-Ropers syndrome (BRS) is a neurodevelopmental disorder predominantly caused by pathogenic variants in the ASXL3 gene, which have been conventionally considered to occur de novo. This study aimed to investigate the potential role of parental mosaicism in BRS inheritance and its clinical implications for genetic counseling. Trio-based whole-exome sequencing (WES) was performed on the proband and both parents to identify candidate variants, which were subsequently validated by Sanger sequencing. ASXL3-targeted ultra-deep sequencing of paternal semen DNA was then carried out to detect low-level mosaicism. Prenatal diagnosis via amniocentesis was used to evaluate transmission of the familial variant. We definitively diagnosed this family by WES and found the lowest level of paternal mosaicism reported to date, with a peripheral blood variant allele frequency (VAF) of 8.17% and a semen VAF of 15.03%. Prenatal diagnosis at 18 weeks of gestation confirmed that the variant was not detected in this pregnancy. This study establishes parental chimerism as an important genetic mechanism for ASXL3-associated disorders and emphasizes the need for ultrasensitive testing in genetic counseling. The findings redefine genetic risk stratification for BRS and provide a basis for accurate family planning based on high-depth sequencing.

Bainbridge-Ropers Syndrome (BRPS) is a genetic condition resulting from truncating variants in the ASXL3 gene. The clinical features include neurodevelopmental and language impairments, behavioral issues, hypotonia, feeding difficulties, and distinctive facial features. In this retrospective study, we analyzed 22 Spanish individuals with BRPS, aiming to perform a detailed clinical and molecular description and establish a genotype-phenotype correlation. We identified 19 ASXL3 variants, nine of which are novel. We documented recurrence in nontwin siblings due to parental mosaicism. The predominant prenatal finding was intrauterine growth restriction (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia (85.7%), and gastroesophageal reflux disease (82.4%). Later in life, intellectual disability, language impairment, autism spectrum disorder (75%), and joint laxity (73.7%) were noted. Individuals with variants in the 3' mutational cluster region (MCR) of exon 12 exhibited more perinatal feeding problems, and those with variants in the 5' MCR of exon 11 displayed lower percentiles in height and occipitofrontal circumference, as well as higher frequency of arched eyebrows. This study is the first characterization of a Spanish BRPS cohort, with more than 50 clinical features analyzed, representing the most detailed phenotypic analysis to date.