ASXL3 – Bainbridge-Ropers Syndrome

Bainbridge-Ropers syndrome (BRPS) is a severe autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in the additional sex combs-like 3 (ASXL3) gene. Clinically, BRPS (MONDO:0014205) presents with profound global developmental delay, feeding difficulties, hypotonia, failure to thrive, microcephaly, and distinctive craniofacial features including arched eyebrows and anteverted nares (PMID:27075689).

Extensive case series and individual reports have identified over 30 unrelated probands harboring de novo truncating or splicing variants in ASXL3, with multiple independent families and recurrence in siblings due to parental mosaicism ([PMID:28100473]; [PMID:39833101]). De novo occurrence is documented by trio exome sequencing and confirmed by Sanger analysis in nearly all cases, supporting a haploinsufficiency mechanism.

Variant spectrum is dominated by truncating alleles: nonsense (e.g., c.3106C>T (p.Arg1036Ter)) ([PMID:29305346]), frameshifts (e.g., c.3006del (p.Arg1004GlufsTer21)) ([PMID:31180560]), and splice-site mutations (e.g., c.3039+1G>T) ([PMID:27075689]), clustering in exons 11–12. Deep‐intronic and missense changes are rare, reinforcing loss of ASXN/ASXH domain integrity as pathogenic.

Segregation analysis includes two sisters sharing the heterozygous p.Arg1036Ter allele, consistent with gonadal mosaicism ([PMID:29305346]), and a Spanish cohort documenting non-twin sibling recurrence with parental mosaicism ([PMID:39833101]). No healthy carriers have been identified, and ASXL3 truncating variants are absent from population databases, underscoring high penetrance.

Functional studies demonstrate that ASXL3 is a component of the Polycomb repressive deubiquitinase (PR-DUB) complex, interacting with BAP1. Patient fibroblasts show reduced ASXL3 transcript levels due to nonsense-mediated decay, increased H2AK119Ub1, and widespread transcriptome dysregulation affecting developmental pathways ([PMID:26647312]).

Animal modeling in Xenopus laevis via ASXL3 knockdown recapitulates neural patterning defects, further corroborating its role in early brain development ([PMID:32132929]).

No studies to date have refuted the association or described alternative inheritance models for BRPS. The cumulative genetic and functional concordance across >15 publications fulfills criteria for a definitive gene-disease relationship.

Key Take-home: Heterozygous de novo truncating variants in ASXL3 cause Bainbridge-Ropers syndrome; early recognition and exome sequencing facilitate accurate diagnosis, genetic counseling, and management.

References

• American Journal of Medical Genetics Part A • 2016 • Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome PMID:27075689
• Journal of Medical Genetics • 2017 • Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome PMID:28100473
• Cold Spring Harbor Molecular Case Studies • 2018 • A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge-Ropers syndrome PMID:29305346
• Molecular Medicine Reports • 2019 • Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay PMID:31180560
• World Journal of Clinical Cases • 2020 • Novel mutation in the ASXL3 gene in a Chinese boy with microcephaly and speech impairment PMID:33392332
• Clinical Genetics • 2025 • Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome PMID:39833101
• Human Molecular Genetics • 2016 • De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome PMID:26647312
• Frontiers in Physiology • 2020 • Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos PMID:32132929

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