LIG4 Syndrome via the LIG4 Gene

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 (http://www.orpha.net/).

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).

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.

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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).