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ASXL1
ASXL transcriptional regulator 1
ASXL1 encodes a chromatin remodelling protein that controls gene expression during development and is associated with both inherited developmental conditions and acquired blood cancers. The ASXL1 gene provides instructions for making a protein that regulates how tightly DNA is packaged in cells, thereby controlling which genes are active at any given time.
ASXL1 is located on the long (q) arm of chromosome 20, at band 20q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
ASXL1 (ASXL transcriptional regulator 1) is located on chromosome 20q11.21 and encodes a 1,541-amino-acid protein involved in chromatin remodelling. The process of chromatin remodelling determines whether specific genes can be transcribed by altering DNA packaging density. Operating through this regulatory mechanism, the ASXL1 protein helps control HOX gene expression, a family of genes essential for proper development before birth. Germline variants in ASXL1 are linked to Bohring-Opitz syndrome, a rare developmental disorder, whilst somatic mutations acquired in blood-forming cells are associated with various haematological malignancies. The gene appears on multiple NHS Genomic Medicine Service PanelApp panels for developmental conditions, reflecting its importance in early human development.
What the gene does
The ASXL1 protein regulates gene activity by modifying chromatin structure, the complex arrangement of DNA and proteins that packages genetic material into chromosomes. Depending on whether DNA strands are wound compactly or sit in a more open configuration, different genes become accessible or inaccessible to the cellular machinery that reads genetic instructions. Tightly condensed chromatin silences neighbouring genes, whilst a looser arrangement permits transcription. ASXL1 orchestrates structural shifts that control HOX gene activation and silencing according to developmental timing and cellular requirements. The protein contains a DEUBAD domain that interacts with other chromatin-modifying complexes and appears to coordinate the removal of ubiquitin marks from histone proteins, thereby influencing gene expression patterns. ASXL1 may also signal for methylation of DNA in promoter regions near genes, a modification that typically represses gene activity. Through these mechanisms, ASXL1 helps ensure that developmental genes are expressed in the correct cells at the correct times, maintaining proper growth and differentiation throughout embryonic and postnatal life.
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Chromosome location
ASXL1 is located at chromosomal band 20q11.21 on the long arm of chromosome 20. The gene spans a substantial genomic region and encodes a large protein of 1,541 amino acids. Its position in the genome places it among other genes involved in haematopoiesis and cellular regulation, though the functional significance of this chromosomal neighbourhood remains an area of ongoing research.
Protein structure
The ASXL1 protein features several defined structural elements across its 1,541-amino-acid length. The N-terminal region contains an HTH HARE-type domain (amino acids 11-86), which likely mediates DNA binding. A DEUBAD domain (amino acids 255-364) is critical for interaction with deubiquitinating enzymes and includes an LXXLL motif (amino acids 284-288). The protein contains regions that interact directly with nucleosomal DNA, including a segment forming a DNA clamp with BAP1 (amino acids 243-246) and another DNA-contact region (amino acids 336-346). A nuclear localisation signal (amino acids 408-415) directs the protein into the nucleus where chromatin remodelling occurs. The protein also features an extended region that interacts with NCOA1 (amino acids 300-658) and an NEF motif (amino acids 310-315). Much of the protein sequence comprises disordered regions, which may provide structural flexibility important for binding multiple protein partners in chromatin-remodelling complexes.
Key variants
Pathogenic variants in ASXL1 fall into two broad categories with distinct clinical consequences. Germline variants, which are inherited or arise de novo in the germline, typically result in truncating mutations that cause Bohring-Opitz syndrome. These variants create premature stop signals, leading to shortened, non-functional protein. Somatic variants acquired during life are frequently found in blood cancers and often affect different regions of the gene, potentially altering protein function rather than eliminating it entirely. The variant spectrum reflects the dual role of ASXL1 in both development and maintenance of blood cell populations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1162_1163del | p.Val388fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1210C>T | p.Arg404Ter | Pathogenic | ★★☆☆ | Bohring-Opitz syndrome |
c.1282C>T | p.Gln428Ter | Pathogenic | ★★☆☆ | not provided |
c.1544_1545del | p.Val515fs | Pathogenic | ★★☆☆ | not provided |
c.1720-1G>A | - | Pathogenic | ★★☆☆ | Bohring-Opitz syndrome |
c.1773C>A | p.Tyr591Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1867C>T | p.Gln623Ter | Pathogenic | ★★☆☆ | not provided |
c.1900_1922del | p.Glu635fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bohring-Opitz syndrome |
c.1934dup | p.Gly646fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2077C>T | p.Arg693Ter | Pathogenic | ★★☆☆ | Myelodysplastic syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Germline pathogenic variants in ASXL1 cause Bohring-Opitz syndrome, a rare autosomal dominant condition characterised by distinctive craniofacial features, intellectual disability, joint abnormalities, and growth challenges. More than 20 causative mutations have been identified, most creating truncated proteins. Separately, somatic ASXL1 mutations acquired in haematopoietic cells are associated with several blood cancers, including acute myeloid leukaemia, chronic myelomonocytic leukaemia, and myelodysplastic syndrome. These acquired mutations represent changes that occur only in blood-forming cells during a person's lifetime and are not passed to offspring. The clinical significance of a given ASXL1 variant depends critically on whether it is germline or somatic.
UK clinical status
ASXL1 appears with Green (high-evidence) classification on multiple NHS Genomic Medicine Service gene panels, reflecting strong clinical evidence for its role in developmental disorders. Relevant panels include Intellectual Disability (R29), Fetal Anomalies (R21), Skeletal Dysplasia (R104), Rare Syndromic Craniosynostosis or Isolated Multisuture Synostosis (R100), and DDG2P. The gene is also listed on panels for Arthrogryposis (R83), Limb Disorders, and Clefting. This broad panel coverage reflects the diverse developmental abnormalities that can result from ASXL1 variants, supporting the use of ASXL1 testing in NHS diagnostic pathways for patients presenting with overlapping features of Bohring-Opitz syndrome or related phenotypes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between germline and somatic ASXL1 variants?
Germline variants are inherited or arise early in development and are present in all cells of the body, causing Bohring-Opitz syndrome. Somatic variants are acquired during life in specific blood-forming cells and are associated with blood cancers but are not passed to offspring.
Is ASXL1 tested on the NHS for developmental conditions?
Yes, ASXL1 is included with Green (high-evidence) status on multiple NHS Genomic Medicine Service panels, including Intellectual Disability, Fetal Anomalies, and Skeletal Dysplasia, meaning it is routinely analysed when these conditions are suspected.
How does ASXL1 control gene expression?
ASXL1 alters chromatin structure by working with enzyme complexes that modify histone proteins, changing how tightly DNA is packaged. This regulates whether developmental genes, particularly HOX genes, are active or silenced at specific times during growth and development.
References
- Inoue D, Matsumoto M, Nagase R. Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. Experimental hematology. 2016. PMID: 26700326
- Russell B, Johnston JJ, Biesecker LG. Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. American journal of medical genetics. Part A. 2015. PMID: 25921057
- Aravind L, Iyer LM. The HARE-HTH and associated domains: novel modules in the coordination of epigenetic DNA and protein modifications. Cell cycle (Georgetown, Tex.). 2012. PMID: 22186017
- Magini P, Della Monica M, Uzielli ML. Two novel patients with Bohring-Opitz syndrome caused by de novo ASXL1 mutations. American journal of medical genetics. Part A. 2012. PMID: 22419483
- Hoischen A, van Bon BW, Rodríguez-Santiago B. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nature genetics. 2011. PMID: 21706002
- Bohring A, Oudesluijs GG, Grange DK. New cases of Bohring-Opitz syndrome, update, and critical review of the literature. American journal of medical genetics. Part A. 2006. PMID: 16691589