Human Molecular Genetics

Figure 1.CAG allele sizes from unaffected and affected individuals for each of the seven CAG expansion disorders (1-88).

Except for SCA6, the similarity between the ranges of disease (>40 CAGs) and normal size alleles at each of the seven TNR diseases suggests a common mechanism of expansion. However, the interval between normal and disease range can also be used to divide these seven disorders into two groups. For example, SBMA, SCA6, DRPLA and SCA3 clearly have mutually exclusive normal and disease range CAG alleles. On the other hand, there is no obvious gap between normal and disease ranges for Huntington's disease (HD), SCA1 and SCA2 (Fig. 1 ).

PENETRANCE, INDIVIDUALITY AND DISEASE

Despite our extensive genetic variability and exposure to different environments, it is remarkable that, for all these disorders, that CAG size is associated so strongly with age of onset-a critera itself subject to significant differences in interpretation. A disease gene has reduced penetrance when a fraction of patients do not manifest the disorder despite inheriting a known disease-causing mutation (89 ). However, for many individuals with TNR diseases, the onset of illness is often late and highly variable. Thus penetrance is age-dependent. In these instances it is appropriate to define reduced penetrance as occurring if persons have inherited a mutation in the disease range but lived beyond the expected lifespan without manifesting any signs of the disease.

Reduced penetrance is the one end of the spectrum of expression of a disease-causing mutation and is clear evidence of how unique individuals accommodate to a particular mutation in the context of the whole genome, environment and experience. The delineation of the molecular basis of these diseases has allowed new and definitive approaches to assessment of penetrance in this class of disorders. For all of the CAG TNR diseases combined, the reported instances of non-penetrance are few, given the large number of individuals molecularly assessed (8 ,30 ,44 ,90 -92 ).

Table 1 Comparison of CAG expansion disorders

	Year cloned	Disease frequency	No of persons analyzed		Molecularly proven new mutations	Zone of reduced penetrance
			Normal	Affected	(IA size)	(CAG size)
SBMA	1991	<1/50 000	>300	>200	not described	not described
DRPLA	1994	rare	>900	>200	not described	possible
HD	1993	1/10 000	>2000	>2000	1-3% (29-35)	36-41
SCA1	1993	<1/100 000	>600	>150	not described	not described
SCA2	1996	<1/100 000	>1000	>200	not described	32-34
SCA3	1994	<1/100 000	>1000	>600	not described	not described
SCA6	1997	<1/100 000	>1000	<90	not described	not described

In DRPLA, two cases of possible non-penetrance have been reported (76 ,90 ). In the first, an individual homozygous for an allele with a CAG size of 57 had onset at age 17; however, neither of his parents, each harbouring 57 repeats, showed any signs of DRPLA at the ages of 71 and 73 (76 ). In another instance, an abstract detailing a single family (90 ) is referred to by Nance as a second case of reduced penetrance (91 ). However, this family demonstrated autosomal recessive hereditary spastic paraplegia, and this is not consistent with an example of reduced penetrance for DRPLA.

In one SCA1 family, an individual had a CAG size of 44 and was healthy at age 66, two standard deviations beyond the average age of risk (30 ). If continued until the expected normal lifespan, this would be compatible with reduced penetrance in this case (30 ).

Of all the CAG expansion diseases, HD demonstrates the greatest number of individuals with reduced penetrance. Several different reports have indicated that a small percentage of people with a CAG size in the affected range may show reduced penetrance (8 ,91 ,91 ,91 ). The likelihood of reduced penetrance is CAG size-related. The CAG size range, where the majority of persons manifest within their expected lifetimes with clinical signs but a few remain asymptomatic, is the zone of reduced penetrance (ZRP) (Fig. 1 ). In HD, this spans from 36 to 41 CAG repeats. At the lower range (36-38 CAGs), it appears that non-penetrance occurs with greatest frequency. Accurate delineation of the ZRP is critical and has practical and biological importance. For example, any individual who inherits a CAG size >41 (80% of affected persons) should not be given false hope by reports of reduced penetrance as this has not been noted to occur in these CAG size ranges.

While penetrance is clearly CAG size-dependent, factors other than CAG size contribute to the age of onset and also influence penetrance rates. For example, for the same CAG size between 36 and 41, different proportions of people manifest with signs and symptoms of this illness. Understanding of the unique factors, both genetic and environmental, which may differentiate between these patients, may be particularly important. It is potentially exciting to contemplate that diseases associated with triplet repeats which have been regarded as diseases solely influenced by mutations in a putative gene may eventually be viewed as diseases with both genetic and other contributing factors such as particular environments, acting over time to result in a clinical phenotype. The emergence of non-penetrance for these disorders places the phenotype seen in the present, as the outcome of numerous influences over time. Childs has referred to this as `hierarchies of diseases derived from three symptoms of organization-the genes, the environment, and development-each with its own imperatives' (92 ), acting over time.

INTERMEDIATE ALLELES

The determination of the molecular basis of these diseases has allowed delineation of the sequence of molecular events in sporadic cases. HD is the only one of the seven CAG TNR disorders for which there are molecularly proven examples of new mutations (15 ,29 ,58 ). In DRPLA and SCA3, there are a few cases of potential sporadic cases, but none have been proven molecularly (42 ,78 ). In HD, `intermediate alleles' (IAs) are defined on the basis of the following criteria: (i) the CAG size range from which new mutations have arisen; (ii) allele sizes larger than commonly seen in the general population but smaller than that seen in patients with HD; and (iii) are found in clinically normal persons (42 ,78 ). All three criteria need to be present for the allele to be termed an IA (Fig. 2 ).

A patient with an IA is not at risk for developing signs and symptoms of the disorder. However, there is a small but significant risk that the offspring will inherit an expanded CAG allele and eventually manifest with the disease. Thus an IA may behave as a `premutation'. However, `premutation' suggests that it is highly unstable and that the offspring are at high risk of developing the disorder, which is not the case. For HD, an IA has never been shown to expand into the disease range through the female germline, while for male transmission of an IA the risk of expansion into the disease range is ~2.5% for every offspring.

Recently, different approaches to the designation of the IA have been suggested. These included replacing IA with the term `mutator' (91 ). However, this would appear to be unwarranted as it implies a `mutator phenotype' associated with significant genetic instability, as observed in many sporadic tumours as well as hereditary non-polyposis colorectal tumours, which is not the case.

IAs clearly are different from CAG sizes in the ZRP. It is inappropriate to term CAG allele sizes that have never been associated with disease as part of a range of reduced penetrance. The definition of penetrance requires that some persons in this CAG range have inherited a known disease-causing mutation. IAs and alleles with reduced penetrance are distinguished by the fact that there are some affected persons in the ZRP while there are no affected individuals harboring IAs. These terms are therefore both useful but are mutually exclusive.

The use of the term `indeterminate allele' should also not be used interchangeably with IA. The use of `indeterminate allele' suggests the importance of the CAG size in that range is not known. However, analysis of large numbers of HD patients has provided reasonable understanding of the behavior and significance of CAG sizes in different ranges.

GAPS, LIFESPAN, RULES AND EXCEPTIONS

Since penetrance is CAG-size-related, the CAG size of the interval between disease and normal state may serve as a predictor of the likelihood of reduced penetrance. For instance, for disorders with no discernible interval between allele sizes on normal and disease chromosomes, such as HD, reduced penetrance may be more frequent, especially in the lowest range of CAGs seen in affected persons. Similarly, in SCA1 and SCA2 where normal and disease ranges are continuous, some examples of reduced penetrance would be expected in the low range of CAG allele sizes seen in affected persons.

By contrast, in DRPLA and SCA3, which both demonstrate a large interval between the normal and disease ranges, there would be less likelihood of observing reduced penetrance, owing to the broad distinction between normal and disease genotypes. We would therefore predict relatively fewer cases of reduced penetrance in DRPLA and SCA3 than in HD and SCA2.

The frequency of detecting persons with reduced penetrance is also related to the expected lifespan. If the expected lifespan is reduced, the likelihood of finding persons with reduced penetrance is increased. For example, in Russia, where the life expectancy for males has recently decreased to 58, the zone of reduced penetrance for HD would increase to 44 CAG repeats (8 ) and more unaffected persons in this range destined for later onset will be detected. Conversely, as the expected lifespan increases, the zone of reduced penetrance will decrease and the number of persons with reduced penetrance will decrease as more persons who have late onset will develop symptoms in their expected lifespan.

If the mechanism of expansion is one of small incremental increases, with greater instability associated with increasing allele length, the probability of finding new mutations (sporadic cases) would also be predicted to be greater for those disorders where clinically normal persons with CAG sizes close to the disease range are found. However, new mutations have not been described in SCA1 and SCA2 (small or no gap) because in all likelihood, in these instances, interruptions of the CAG tract confers stability on normal sized alleles (Table 2 ). An additional step, namely loss of the interruption is needed to confer increased instability on normal sized alleles (Table 2 ).

Table 2 Sequence comparison of the CAG tract for the seven CAG expansion disorders

	Usual sequence of CAG tract
	Disease	Normal
HD	interrupted by penultimate CAA	interrupted by penultimate CAA
SCA1	pure CAG	1-3 CAT interruptions in middle of (CAG)n
SBMA	pure CAG	pure CAG
SCA2	pure CAG	CAA interruptions
		(CAG)nCAA(CAG)nCAA(CAG)n
		(CAG)nCAA(CAG)n
DRPLA	pure CAG	pure CAG
SCA3	pure CAG	pure CAG
SCA6	not described	not described

In a letter by William Harvey in 1657 it was written that `there is [no] better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of Nature by careful investigation of rarer forms of disease' (93 ). This wisdom is particularly pertinent for the CAG expansion disorders. If one detects a person with a larger than expected CAG size who does not manifest with this disorder until very late or not at all, this could be indicative of other factors moderating expression. This could provide a clue into potential mutations in other genes such as interacting proteins that may modulate the disease phenotype. Delineation of these other factors moderating the course of the illness will open up new pathways of understanding and novel approaches to therapy.

ACKNOWLEDGEMENTS

We thank Drs Olaf Riess, Guy Rouleau, Huda Zoghbi and other colleagues in our laboratory, especially Elisabeth Almqvist and Ryan Brinkman for helpful discussions. This work is supported by the MRC (Canada), the Canadian Genetic Diseases Network. SEA is an MRC post-doctoral fellow. MRH is an established investigator for the B.C. Children's Hospital.

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*To whom correspondence should be addressed. Tel: +1 604 822 9240; Fax: +1 604 822 9238; Email: mrh@ulam.generes.ca

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