Huntington's Disease CAG Repeat Sizing

The Huntington's Disease (HD) gene was mapped to chromosome 4p16.3 in 1983 but eluded identification until 1993. When finally identified, the gene ( IT15) was found to contain a CAG repeat within its 5'-end coding sequence (Cell 72:971-983). This CAG repeat is expanded in individuals with HD who may or may not be symptomatic. The presence of a CAG repeat expansion is found in virtually all symptomatic HD individuals (N. Engl. J. Med. 330:1401-1406).

Normal HD gene CAG repeats range from 10 - 29 repeats. A few normal individuals (<1%) have intermediate HD gene CAG repeats of 30 35 repeats. Individuals affected with HD typically have at least one HD gene CAG repeat of 36 repeats or greater. A recent review of> 1,100 affected individuals showed that none had a CAG repeat of <36 repeats. However, it was also found that in a few rare instances (10 cases) individuals having repeats of 36 39 repeats had remained asymptomatic by standard clinical criteria at advanced age. In one exceptional case, a 95 year old patient had 39 repeats (Rubinsztein et. al., 1996; Am. J. Hum. Genet. 59:16-22). Individuals who have an HD gene CAG repeat size close to the normal/affected boundary should be counseled in light of the sizes of the HD gene CAG repeat sizes found in any affected relatives and/or by considering clinical findings. There is a tendency to an earlier age-of-onset of HD symptoms with increasing CAG repeat number. A current review of 1,049 persons (the majority of whom were symptomatic) has provided a determination of the likelihood of an age-of-onset for a given CAG repeat size for repeats between 39 50 repeats (Brinkman et al., 1997; Am. J. Hum. Genet. 60:1202-1210). Summary data are reproduced in the table below. For complete information, please refer to the cited article.

CAG Repeat Size Median Age at Onset *

(years)

(95% confidence interval)
39
66 (72-59)
40
59 (61-56)
41
54 (56-52)
42
49 (50-48)
43
44 (45-42)
44
42 (43-40)
45
37 (39-36)
46
36 (37-35)
47
33 (35-31)
48
32 (34-30)
49
28 (32-25)
50
27 (30-24)

*Age by which 50% of individuals will be affected

A PCR-based test on DNA in peripheral blood permits an unequivocal confirmation of a diagnosis of HD in symptomatic individuals or can provide presymptomatic testing in appropriate cases. (Please consult with CompGene). A positive result with this diagnostic test in a symptomatic individual has serious genetic implications for immediate family members. The HD gene CAG repeat sizing at CompGene excludes the known adjacent polymorphic CCG repeat that can contribute to an inaccurate determination of HD gene CAG repeat sizes in individuals who may have an HD gene CAG repeat allele close to the normal/affected boundary. HD gene CAG repeat sizes are accurate within +/- 1 repeat.

In the examples below, six different results for symptomatic individuals are depicted with normal alleles ranging between 18 and 33 repeats and affected alleles ranging between 40 and 60 repeats. An overexposed DNA sequencing ladder used for accurate sizing of CAG repeats is depicted on the right of the figure.