ASXL1 – Bohring-Opitz Syndrome

ASXL1 (Additional Sex Combs-Like 1) is robustly associated with Bohring-Opitz syndrome, a rare autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability, feeding difficulties, characteristic facial features, and failure to thrive. Heterozygous de novo loss-of-function variants in ASXL1 disrupt chromatin regulation, leading to the Bohring-Opitz phenotype.

1. Clinical Validity

A Definitive gene-disease association is supported by over 130 unrelated probands with heterozygous de novo truncating ASXL1 variants, replicated in multiple cohorts and consistent functional studies (PMID:21706002, PMID:36751885).

2. Genetic Evidence

Bohring-Opitz syndrome arises from autosomal dominant inheritance, predominantly de novo. Segregation analysis reveals a single case of maternal germline mosaic transmission without additional affected relatives (PMID:29681100). Aggregate case reports and series encompass >100 probands with loss-of-function variants, including nonsense and frameshift alleles. A representative recurrent variant is c.1934dup (p.Gly646TrpfsTer12) in multiple patients (PMID:29681105).

3. Functional Evidence

Mechanistically, ASXL1 truncating variants impair chromatin modification. Patient fibroblast mRNA analysis confirmed aberrant splicing for the de novo variant c.1720-2A>G (PMID:31692235). Genome-wide DNA methylation profiling identified a distinct signature in 17 ASXL1-variant individuals, aligning with functional dysregulation of HOX gene clusters (PMID:35361921).

4. Conflicting Evidence

Somatic mosaic ASXL1 truncating variants appear in population databases due to age-related hematopoietic clonal expansion, complicating germline variant interpretation but not undermining the clear pathogenicity in Bohring-Opitz syndrome (PMID:28229513).

5. Integration & Clinical Utility

ASXL1 loss-of-function causes Bohring-Opitz syndrome via haploinsufficiency impacting polycomb repressive complex activity and epigenetic regulation. De novo truncating variants reliably predict BOS, guiding diagnostic sequencing and genetic counseling, including recurrence risk assessment in mosaic cases. Functional assays and DNA methylation signature offer tools for variant classification.

Key Take-home: ASXL1 de novo truncating variants are a definitive, clinically actionable cause of Bohring-Opitz syndrome, informing diagnosis, management, and genetic counseling.

References

• Nature Genetics | 2011 | De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. PMID:21706002
• American Journal of Medical Genetics Part A | 2023 | Clinical findings in 39 individuals with Bohring-Opitz syndrome from a global patient-driven registry with implications for tumor surveillance and recurrence risk. PMID:36751885
• American Journal of Medical Genetics Part A | 2020 | Extending the phenotypic spectrum of Bohring-Opitz syndrome: Mild case confirmed by functional studies. PMID:31692235
• European Journal of Human Genetics : EJHG | 2022 | DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes. PMID:35361921
• American Journal of Medical Genetics Part A | 2018 | Bohring-Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother. PMID:29681100

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