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LIG4
DNA ligase 4
LIG4 is located on the long (q) arm of chromosome 13, at band 13q33.3. Arm ratio per GRCh38 - banding schematic.
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Overview
LIG4 is located on chromosome 13 and encodes DNA ligase IV, a specialised enzyme responsible for the final step in non-homologous end-joining (NHEJ), the primary pathway cells use to repair double-strand DNA breaks. These breaks arise naturally during cellular processes such as V(D)J recombination in developing immune cells, and also result from exposure to ionising radiation or certain chemicals. Because ligase IV activity is crucial for maintaining genomic stability, pathogenic changes in LIG4 lead to severe clinical consequences. Individuals with biallelic LIG4 variants typically present with immunodeficiency, microcephaly, developmental delay, and heightened sensitivity to radiation. The condition follows an autosomal recessive inheritance pattern, meaning two altered copies of the gene are required for disease manifestation.
What the gene does
DNA ligase IV catalyses the formation of phosphodiester bonds between adjacent DNA nucleotides, effectively sealing breaks in the sugar-phosphate backbone of DNA. The enzyme functions as part of the NHEJ repair complex, working alongside partners including XRCC4 and XLF to coordinate the ligation step after broken DNA ends have been processed and aligned. During V(D)J recombination, ligase IV is indispensable for joining gene segments that create the diverse repertoire of antibodies and T-cell receptors in the immune system. The protein's catalytic activity depends on its ability to bind DNA ends and position them correctly for the ligation reaction. Beyond immune development, ligase IV contributes to general DNA repair throughout the body, protecting cells from mutations that could lead to cancer or cell death. Cells lacking functional ligase IV accumulate unrepaired breaks, triggering checkpoints that halt cell division or initiate programmed cell death, which particularly affects tissues with high rates of cell turnover.
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Chromosome location
The LIG4 gene is positioned at chromosomal band 13q33.3 on the long arm of chromosome 13. The encoded protein comprises 911 amino acids and is expressed in most tissues, with particularly high levels in rapidly dividing cells such as those in lymphoid organs and the developing brain.
Protein structure
DNA ligase IV is a 911-amino-acid protein organised into several functional regions. The catalytic core, essential for the ligation reaction, includes a critical region spanning amino acids 610 to 620 that is required for enzymatic activity. The C-terminal portion of the protein contains two tandem BRCT domains: BRCT 1 extends from amino acids 654 to 743, whilst BRCT 2 spans amino acids 808 to 911. These BRCT domains mediate protein-protein interactions, particularly the binding to XRCC4, which is essential for stabilising ligase IV and enabling its recruitment to sites of DNA damage. The modular architecture allows the enzyme to coordinate catalytic function with partner recognition, ensuring efficient and accurate DNA repair.
Key variants
Pathogenic variants in LIG4 are rare and typically result in loss of enzyme function. Most disease-causing changes are missense variants that disrupt either the catalytic activity or the protein's ability to interact with repair partners. Some variants affect the BRCT domains, impairing XRCC4 binding and destabilising the repair complex. The severity of clinical features often correlates with residual ligase IV activity, with complete loss of function leading to early lethality and hypomorphic variants permitting survival with variable immunodeficiency and neurodevelopmental impairment.
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.1512_1513dup | p.Arg505fs | Pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.1578G>A | p.Trp526Ter | Pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.1746_1750del | p.Glu582fs | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.2094C>G | p.Tyr698Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.220C>T | p.Gln74Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.2585_2586del | p.His862fs | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.597_600del | p.Gln200fs | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.724_725del | p.Leu242fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple myeloma |
c.833G>T | p.Arg278Leu | Pathogenic | ★★☆☆ | DNA ligase IV deficiency |
c.877C>T | p.Arg293Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DNA ligase IV deficiency |
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
Biallelic pathogenic variants in LIG4 cause LIG4 syndrome, a rare autosomal recessive disorder characterised by severe combined immunodeficiency, microcephaly, developmental delay, and growth retardation. Affected individuals present with recurrent infections due to impaired lymphocyte development, and many exhibit unusual facial features and bone marrow abnormalities. The immunodeficiency arises because ligase IV is essential for completing V(D)J recombination, without which functional antibodies and T-cell receptors cannot be generated. Microcephaly and developmental problems reflect the vulnerability of the developing brain to unrepaired DNA damage. Some individuals with LIG4 syndrome also demonstrate increased cancer susceptibility, particularly lymphoid malignancies, owing to genomic instability. Clinical severity varies depending on the specific variants present and the degree of residual enzyme function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic LIG4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
LIG4 is recognised across multiple NHS Genomic Medicine Service gene panels, reflecting its clinical significance in several domains. The gene holds green classification status in panels including Primary immunodeficiency or monogenic inflammatory bowel disease, Intellectual disability, Severe microcephaly, and Haematological malignancies cancer susceptibility, among others. This broad panel representation indicates that LIG4 testing may be considered in individuals presenting with immunodeficiency, developmental delay, microcephaly, or haematological abnormalities, depending on clinical context and the specific panel criteria applied by the referring clinician.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean if I carry one altered copy of LIG4?
Carrying a single pathogenic LIG4 variant makes you a carrier for LIG4 syndrome, but you will not develop the condition yourself because the other copy of the gene typically functions normally. Carriers generally have no symptoms and are identified through carrier screening or family testing.
How is LIG4 syndrome inherited?
LIG4 syndrome follows an autosomal recessive pattern, meaning an affected individual has inherited one altered LIG4 gene from each parent. When both parents are carriers, each pregnancy has a 25% chance of producing an affected child, a 50% chance of producing a carrier, and a 25% chance of producing a child with two typical copies.
Can LIG4 variants affect cancer risk?
Research suggests that individuals with biallelic LIG4 variants have increased susceptibility to certain cancers, particularly lymphoid malignancies, due to impaired DNA repair and genomic instability. Carrier status for a single variant has not been definitively linked to elevated cancer risk in the general population.