Subtelomeric Region Anomalies, FISH
Evaluation of cases of nonspecific moderate-to-severe mental retardation or nonspecific dysmorphic features when standard chromosome results are normal
Evaluation of parents or other family members of a patient who has been previously diagnosed with a subtelomere abnormality
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Telomere caps of (TTAGGG)n repeats constitute 3 Kb to 20 Kb at the ends of each human chromosome. Centromeric to the telomere caps are 100 Kb to 300 Kb of telomere-associated repeats (TAR). Unique DNA sequences are centromeric to the TAR ending. The telomere-specific DNA probes are derived from the area near the junction of the TARs and unique sequences.(1)
Because of high gene concentrations in telomeric regions(2), there is an intense interest in subtle abnormalities involving the telomeres. For example, subtle abnormalities have been reported involving the telomeres in 7.4% of a large population of children with moderate-to-severe mental retardation.(3) Abnormalities involving the telomere regions also are suspected in individuals with nonspecific dysmorphic features or couples with multiple miscarriages who are karyotypically normal.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
A deletion results in the loss of a p-arm or q-arm specific probe, and a cryptic translocation causes an exchange between the involved chromosome arms. Duplications, derivative chromosomes, and insertions of subtelomeric regions also can be detected.
Family studies may be necessary following abnormal results from this FISH study, as parents may carry balanced translocations or deletions that are found in their children.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A standard chromosome analysis must be performed first to rule out microscopically observable karyotypic abnormalities.
Microdeletions that are outside of the probe location are undetectable and this test cannot detect DNA molecular alterations such as point mutations.
If original specimen is of low volume or has low number of suitable metaphases, another specimen may be necessary for this test, since this test requires large quantities of metaphases.
We have validated the hybridization efficiency of the telomere-specific FISH probe set in a variety of cases.
A total of 22 couples with multiple miscarriages were analyzed, who were karyotypically normal and had no apparent abnormality of the telomere regions. However, 5 of these individuals had a deletion of the 2q telomere-specific probe (D2S2986). Additionally, the deletion was observed in a child with multiple dysmorphic features, as well as his clinically normal parent. As a result, deletions involving this probe are presumed to be normal population variants. This has proven to be a normal deletion variant because it was not deleted when the 2q subtelomere-specific probe of another commercial company was used. For several chromosome telomeres (2p, 3q, 4p and q, 8p and q, 9q, 11p and q, 12p, 15q, 16q, 17p and q, 18p, 20q and 22q), some cross-hybridizations to other chromosomal regions occurred, but they were distinct, often weak, and easily discernible. Other potential "normal variants" have been reported in the literature, so parental testing and clinical correlation is recommended whenever a subtelomere abnormality is identified.
Our experience based on the analysis of 2237 patients indicates that subtelomeric abnormalities occur in approximately 7.4% of individuals tested. The anomalies found included deletions, duplications, derivative chromosomes, and reciprocal translocations. However, no more than 50% of these were subtle or cryptic. This test is also helpful in describing subtelomere anomalies in a timely manner that are ambiguous by banded chromosome analysis.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Knight SJ, Lese CM, Precht S, et al: An optimized set of human telomere clones for studying telomere integrity and architecture. Am J Hum Genet 2000;67:320-332
2. Saccone S, DeSario A, Della Valle G, et al: The highest gene concentrations in the human genome are in telomeric bands of metaphase chromosomes. Proc Natl Acad Sci USA 1992;89:4913-4917
3. Knight SJ, Regan R, Nicod A, et al: Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354:1676-1681