Ataxia-Telangiectasia-Like Disorder via the MRE11/MRE11A Gene

Ataxia-telangiectasia-like disorder (ATLD) is similar to the disease ataxia-telangiectasia (A-T) in that patients show progressive cerebellar ataxia; however, they do not show telangiectasias and show normal immunoglobulin levels, later-onset disease and a milder clinical course compared to A-T. At the cellular level, there is chromosomal instability, increased sensitivity to ionizing radiation, defective induction of stress-activated signal transduction pathways, and radioresistant DNA synthesis (Taylor et al. DNA Repair 3(8-9):1219-25, 2004).

Ataxia-telangiectasia-like disorder (ATLD) is caused by variants in the MRE11/MRE11A gene, which is involved in homologous recombination, telomere length maintenance, cell cycle checkpoint control, and DNA double-strand break repair (Taylor et al. DNA Repair 3(8-9):1219-25, 2004). The MRE11A protein forms a complex with the RAD50 and NBS1 proteins to form the MRN complex, which is required for proper DNA repair. The protein ATM when mutated is responsible for ataxia-telangiectasia, which acts upstream of the MRN complex and is responsible for MRN activation through phosphorylation. The MRN complex also has a role in ATM recruitment to DNA damage foci (Wu et al. Mol Cell. 2012 May 11;46(3):351-61, 2012) and has been shown to be associated with mismatch repair proteins (Wu et al. Mol Cancer Res 9(11):1443-8, 2011). ATLD has an autosomal recessive mode of inheritance and variants reported to date include missense, splicing, and a small deletion (Human Gene Mutation Database).

Analytical sensitivity should be high, because the variants reported are readily detectable by gene sequencing. Clinical sensitivity is unknown at this time since ATLD is a rare disease and relatively few patients have been reported.

This test provides full coverage of all coding exons of the MRE11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.