Cryptic telomere imbalance: A 15‐year update

AbstractIt has been 15 years since we proposed that assays of telomere integrity might reveal cryptic translocations and deletions as a significant cause of mental retardation (MR) in patients with normal G‐banded karyotypes. Development of unique genomic probes adjacent to the subtelomeric repeats of each chromosome arm allowed multiplex FISH analyses that confirmed such cryptic telomeric imbalances in 3–6% of all unexplained MR. Although such “telomere FISH” analysis quickly became standard of care, limitations of this technology platform included a lack of information on the size and gene content of the deleted/duplicated segments and the failure to detect interstitial deletions not involving the most distal unique clone. The development of “molecular ruler” clone sets for every human telomere provided the foundation for accurate determination of size and gene content of each imbalance, as well as the detection of interstitial deletions within these regions. Array comparative genomic hybridization (aCGH) has emerged as a powerful technology to assess single copy changes (monosomy or trisomy) at targeted loci such as telomeres or across the whole genome. This technology now repla