On this page
NHEJ1
non-homologous end joining factor 1
NHEJ1 is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 2 in the library →Available at Jeen Health
Clinical tests that include this
Overview
NHEJ1, located on chromosome 2, produces a protein known as Cernunnos or XLF (XRCC4-like factor). This protein participates in non-homologous end joining, a major pathway cells use to mend DNA double-strand breaks throughout the cell cycle. The gene's full name, non-homologous end joining factor 1, directly reflects this core function. Pathogenic changes in NHEJ1 follow an autosomal recessive inheritance pattern, meaning affected individuals carry mutations in both gene copies. The protein's importance becomes evident during lymphocyte development, where programmed DNA breaks occur as part of normal immune system maturation. Disruption of NHEJ1 function can therefore compromise both DNA integrity and immune competence.
What the gene does
The NHEJ1 protein works as part of a multi-component molecular machine that detects and repairs DNA double-strand breaks. When such breaks occur, the protein is recruited to damage sites where it assists in holding broken DNA ends together while other repair factors process and rejoin them. NHEJ1 physically interacts with XRCC4 and DNA ligase IV, forming a complex that completes the final ligation step of repair. Beyond structural support, the protein appears to stabilise this repair assembly and may help regulate how DNA ends are aligned before joining. The globular head region and coiled coil domain enable these protein-protein interactions, whilst the C-terminal tail contributes to overall complex stability. This repair pathway operates throughout the cell cycle and proves particularly crucial during V(D)J recombination, the process by which developing immune cells generate diverse antibody and receptor repertoires through controlled DNA cutting and rejoining. Without functional NHEJ1, cells accumulate unrepaired breaks, triggering apoptosis or genomic instability.
Video: Genetics 101
Chromosome location
NHEJ1 resides at chromosomal position 2q35 on the long arm of chromosome 2. The gene spans a relatively compact genomic region and encodes a 299-amino-acid protein. This chromosomal band contains multiple genes involved in diverse cellular processes, though NHEJ1's specific role in DNA repair distinguishes it functionally within this neighbourhood.
Protein structure
The NHEJ1 protein comprises 299 amino acids organised into several distinct regions. The globular head domain occupies residues 1 through 135, providing a structured platform for molecular interactions. Adjacent to this sits a coiled coil region spanning amino acids 128 to 170, which typically mediates protein dimerisation or complex assembly. The C-terminal tail extends from position 224 to 288, followed by a disordered region from residues 255 to 299 that likely confers flexibility for dynamic interactions. At the extreme C-terminus lies the XLM motif, encompassing amino acids 289 through 299, which has been implicated in binding to XRCC4. This modular architecture enables NHEJ1 to serve as both a structural scaffold and a regulatory component within the DNA repair machinery.
Key variants
Pathogenic variants in NHEJ1 are rare but clinically significant when present in both gene copies. Documented mutations include deletions, nonsense changes, and missense substitutions that disrupt protein stability or interaction interfaces. Because the protein operates within a tightly coordinated repair complex, even subtle alterations can impair overall pathway function. The spectrum of identified variants reflects the gene's relatively recent characterisation, with ongoing clinical sequencing likely to reveal additional pathogenic alleles.
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.11dup | p.Glu5fs | Pathogenic | ★★☆☆ | Severe combined immunodeficiency disease |
c.134G>A | p.Trp45Ter | Pathogenic | ★★☆☆ | Cernunnos-XLF deficiency |
c.390+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.526C>T | p.Arg176Ter | Pathogenic | ★★☆☆ | Cernunnos-XLF deficiency |
c.530-2A>T | - | Pathogenic | ★★☆☆ | Cernunnos-XLF deficiency |
c.532C>T | p.Arg178Ter | Pathogenic | ★★☆☆ | Cernunnos-XLF deficiency |
g.(?_220011382)_(220011480_?)del | - | Pathogenic | ★☆☆☆ | Cernunnos-XLF deficiency |
c.31C>T | p.Gln11Ter | Pathogenic | ★☆☆☆ | Cernunnos-XLF deficiency |
c.489_490del | p.Glu163fs | Pathogenic | ★☆☆☆ | Cernunnos-XLF deficiency |
c.501C>A | p.Tyr167Ter | Pathogenic | ★☆☆☆ | Cernunnos-XLF 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 NHEJ1 give rise to a spectrum of severe autosomal recessive conditions. Affected individuals typically present with combined immunodeficiency characterised by profound T- and B-cell defects, rendering them vulnerable to recurrent and life-threatening infections. Many also exhibit microcephaly, reflecting impaired neuronal survival during brain development when DNA breaks accumulate. Additional features can include growth retardation and increased sensitivity to ionising radiation. The severity of these manifestations underscores NHEJ1's critical role in maintaining genomic stability, particularly in rapidly dividing cell populations such as developing lymphocytes and neural progenitors.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NHEJ1 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
Within the NHS Genomic Medicine Service, NHEJ1 appears on multiple PanelApp panels reflecting its diverse clinical presentations. The gene holds green classification on the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), acknowledging its role in severe immune defects. It also features on the Severe microcephaly panel (R88), reflecting the neurological consequences of impaired DNA repair. Additional green ratings appear on the Fetal anomalies panel (R21) and the COVID-19 research panel, the latter likely relating to investigation of immune response variability. These panel memberships guide when NHEJ1 sequencing is clinically indicated for affected families in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does autosomal recessive inheritance mean for NHEJ1?
Autosomal recessive inheritance means a person must inherit a pathogenic variant in both copies of NHEJ1 (one from each parent) to develop associated conditions. Carriers with only one altered copy typically remain healthy but can pass the variant to their children.
Why does NHEJ1 dysfunction particularly affect the immune system?
Developing immune cells undergo programmed DNA breaks as part of V(D)J recombination, which generates antibody and receptor diversity. Without functional NHEJ1 to repair these breaks, lymphocytes cannot mature properly, resulting in severe combined immunodeficiency.
Is NHEJ1 testing available through the NHS?
NHEJ1 sequencing is available through NHS genomic testing when clinical features align with the gene's panel memberships, such as severe combined immunodeficiency or microcephaly. A healthcare provider can assess eligibility and arrange appropriate referral to clinical genetics services.