ASXL3 – Syndromic Intellectual Disability

Heterozygous de novo loss-of-function variants in ASXL3 underlie a clinically recognizable syndromic intellectual disability, originally termed Bainbridge-Ropers syndrome. In a cohort of six unrelated individuals, whole-exome sequencing identified novel truncating ASXL3 mutations associated with profound global developmental delay, feeding difficulties in infancy, hypotonia, failure to thrive and a characteristic craniofacial gestalt ([PMID:27901041]). Key features of Bohring-Opitz syndrome were absent, establishing ASXL3 deficiency as a distinct entity within syndromic intellectual disability.

The inheritance is autosomal dominant with de novo occurrence in all reported cases. No familial segregation has been observed beyond rare instances of parental mosaicism, underscoring the high penetrance of heterozygous truncating alleles.

Genetic evidence includes six probands harboring de novo truncating variants such as c.956G>A (p.Trp319Ter) ([PMID:27901041]), with an additional nine cases documented in four independent reports. All variants are absent from population databases and result in premature termination codons distributed throughout ASXL3, consistent with haploinsufficiency.

Functional studies in patient-derived fibroblasts demonstrate that mutant ASXL3 transcripts undergo nonsense-mediated decay, leading to reduced protein levels. Loss of ASXL3 impairs the PR-DUB complex, causing a significant increase in histone H2A lysine 119 mono-ubiquitination (H2AK119Ub1) and widespread transcriptional dysregulation affecting developmental and proliferation pathways ([PMID:26647312]).

Integration of genetic and experimental data supports a definitive gene–disease relationship. More than 15 unrelated de novo truncating ASXL3 variants produce a consistent clinical phenotype, and functional concordance with human features has been demonstrated. Additional evidence, including animal models, is emerging but exceeds current ClinGen scoring limits.

Key Take-home: ASXL3 haploinsufficiency due to de novo truncating variants definitively causes a syndromic intellectual disability with distinctive features; ASXL3 should be included in diagnostic gene panels for unexplained neurodevelopmental disorders.

References

• European journal of human genetics • 2017 • Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. PMID:27901041
• Human molecular genetics • 2016 • De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. PMID:26647312

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