LIG4 Syndrome via the LIG4 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT Prenatal
8565 LIG4$890 8147981479,81479 Add to Order

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average


Genetic Counselors


Clinical Features and Genetics

Clinical Features

LIG4 syndrome, also known as Ligation IV syndrome, is characterized by microcephaly, unusual facial features, growth and developmental delay, skin anomalies, pancytopenia, and combined immunodeficiency. Facial features have been described as "bird like" (beak-like nose and micrognathia). An affected individual's skin is photosensitive and can have psoriatic-like lesions. Additionally, patients may have telangiectasias, leukemia, lymphoma, and bone marrow abnormalities (O’Driscoll et al. 2001; Chistiakov et al. 2009). Malignancies have been reported in 25% of reported cases, although cancer risks may be higher because most patients have an early death (Murray et al. 2014). LIG4 syndrome is a clinically heterogeneous disorder as a patient has also been described to have lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactyly, dysmorphic appearance, and erythema (IJspeert et al. 2013). It is an extremely rare syndrome (i.e. <20 cases described) with an estimated prevalence of 1 in 1,000,000 (


LIG4 syndrome is an autosomal recessive disorder caused by pathogenic variants in the LIG4 gene. This gene encodes a ligase that is involved in double stranded break repair during V(D)J recombination and non-homologous end-joining (NHEJ) (IJspeert et al. 2013). The ligase forms a complex with other NHEJ proteins, such as the X-ray repair cross complementing protein 4 (XRCC4) and is important in the final step in ligating DNA strands during NHEJ (Helleday et al. 2007). Cell lines from affected patients show radiosensitivity and chromosome instability (O’Driscoll et al. 2001). Biallelic null alleles are embryonic lethal, so that individuals with LIG4 syndrome have at least one hypomorphic allele. Pathogenic variants observed in the C-terminal and XRCC4-binding domain have a greater deleterious effect than variants outside of these regions (Chistiakov et al. 2009). Reported pathogenic variants include missense, nonsense, and small insertions and deletions (Human Mutation Gene Database).

Testing Strategy

This test provides full coverage of all coding exons of the LIG4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV

Clinical sensitivity is unknown due to the limited number of cases reported. Analytical sensitivity should be high as all reported mutations are detectable by sequencing.

Indications for Test

Individuals suspected of having LIG4 syndrome. Family members may also be tested to determine carrier status of an identified variant in the LIG4 gene. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in LIG4. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.


Official Gene Symbol OMIM ID
LIG4 601837
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Lig4 Syndrome AR 606593

Related Tests

Ataxia Telangiectasia Syndrome via the ATM Gene
Nijmegen Breakage Syndrome via the NBN Gene
Seckel Syndrome, Primary Microcephaly and Familial Cutaneous Telangiectasia and Cancer Syndrome via the ATR Gene


  • Chistiakov DA, Voronova NV, Chistiakov AP. 2009. Ligase IV syndrome. European Journal of Medical Genetics 52: 373–378. PubMed ID: 19467349
  • Helleday T, Lo J, Vangent D, Engelward B. 2007. DNA double-strand break repair: From mechanistic understanding to cancer treatment. DNA Repair 6: 923–935. PubMed ID: 17363343
  • Human Gene Mutation Database (Bio-base).
  • IJspeert H, Warris A, Flier M, Reisli I, Keles S, Chishimba S, Dongen JJ, Gent DC, Burg M. 2013. Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. Hum Mutat 34: 1611–1614. PubMed ID: 24027040
  • Murray JE, Bicknell LS, Yigit G, Duker AL, Kogelenberg M van, Haghayegh S, Wieczorek D, Kayserili H, Albert MH, Wise CA, Brandon J, Kleefstra T, Warris A, van der Flier M, Bamforth JS, Doonanco K, Adès L, Ma A, Field M, Johnson D, Shackley F, Firth H, Woods CG, Nürnberg P, Gatti RA, Hurles M, Bober MB, Wollnik B, Jackson AP. 2014. Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Human Mutation 35: 76–85. PubMed ID: 24123394
  • O’Driscoll M, Cerosaletti KM, Girard P-M, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P. 2001. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Molecular Cell 8: 1175–1185. PubMed ID: 11779494
  • Orphanet


Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

Specimen Types

Specimen Requirements and Shipping Details

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