ASXL2 – Shashi-Pena syndrome

ASXL2 encodes a member of the Additional sex combs-like family of epigenetic regulators that cooperate with Polycomb and other chromatin modifiers to control transcriptional programs during development. Shashi-Pena syndrome (SHAPNS) is a neurodevelopmental disorder characterized by global developmental delay, feeding difficulties, hypotonia, and distinctive facial features including a glabellar nevus flammeus. Genetic studies since 2016 have implicated heterozygous truncating variants in ASXL2 as causative.

SHAPNS follows an autosomal dominant, de novo inheritance pattern. To date, 10 unrelated probands harboring de novo truncating ASXL2 variants have been reported across five independent publications (PMID:27693232, PMID:35182806, PMID:37493007, PMID:36798937, PMID:33751773), with no evidence of transmission in multiplex families.

All reported pathogenic variants are predicted loss-of-function truncations, including nonsense and frameshift mutations distributed across exons 11–13. No recurrent or founder alleles have been described, and no missense variants have been implicated. Key phenotypic features beyond developmental delay include feeding difficulties, hematologic abnormalities (granulocytopenia, thrombocytopenia), hypotonia, cerebellar hypoplasia, and single transverse palmar crease.

Functional assays support a dominant-negative mechanism. mRNA studies demonstrate escape from nonsense-mediated decay and bi-allelic expression of mutant transcripts, consistent with interference of wild-type ASXL2 function (PMID:27693232). Additional models show that ASXL2 is required for Polycomb repressive complex 2 recruitment and H3K27me3 deposition, aligning with the epigenetic dysregulation observed in patients.

No conflicting evidence has been reported. The convergence of de novo genetic findings, consistent loss-of-function mechanism, and functional concordance supports a Strong gene–disease association.

Key Take-home: Heterozygous de novo truncating variants in ASXL2 underlie Shashi-Pena syndrome via a dominant-negative epigenetic mechanism, guiding diagnostic evaluation and genetic counseling.

References

• American Journal of Human Genetics • 2016 • De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. PMID:27693232
• European Journal of Medical Genetics • 2022 • A de novo and novel nonsense variants in ASXL2 gene is associated with Shashi-Pena syndrome. PMID:35182806
• Molecular Genetics & Genomic Medicine • 2023 • Identification of a de novo variant in the ASXL2 gene related to Shashi-Pena syndrome. PMID:37493007
• Translational Pediatrics • 2023 • A newborn with a pathogenic variant in ASXL2 expanding the phenotype of SHAPNS: a case report and literature review. PMID:36798937
• American Journal of Medical Genetics. Part A • 2021 • Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. PMID:33751773

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