CAG Counts: Intermediate alleles

It has been awhile since a review of CAG counts in Huntington's Disease was published, so the new article by Dr. Michael Hayden and colleagues is very helpful. Here's a review of the latest information about intermediate CAG repeat counts.

It has been awhile since a review of CAG counts in Huntington's Disease was published, so the new article by Dr. Michael Hayden and colleagues is very helpful. The normal, intermediate, and reduced penetrance ranges have changed over time and there have also been errors in publications. The authors present the most current information in the table below.

UnaffectedNormal26 and below
Intermediate27 – 35
AffectedReduced Penetrance36 – 39
Full Penetrance40 and above

Individuals receive two copies of the huntingtin's gene, one from each parent. A copy of the gene is called an allele. Since Huntington's Disease is a dominant disorder, only one HD allele is necessary for the individual to develop the disease.

If an individual has alleles in which the CAG repeats are 26 or below, then they will not develop Huntington's Disease nor will any of their children.

If an individual has an allele with 27 to 35 repeats, it falls within the intermediate range. The gene is normal and the individual will not develop Huntington's Disease. There have been no reported cases of HD in individuals with 35 CAG repeats or less.

It is estimated that between 1 and 3.9 percent of the general population has a huntingtin's gene with CAG repeats that fall into the intermediate range.

However, the CAG repeats on an intermediate allele could increase if transmitted to one's offspring, possibly leading to Huntington's Disease in the next or subsequent generations. Alleles with CAG repeats in the intermediate range are sometimes referred to as normal mutable alleles.

Individuals with an allele with 36-39 repeats fall into the reduced penetrance range. Some people in this range will develop the disease and some will not.

An allele with 40 or more CAG repeats is a full penetrance Huntington's Disease gene. If the person lives long enough and doesn't die of another cause, for example, a traffic accident, he will develop Huntington's Disease. A child of a parent with one HD allele and one normal allele has a 50 percent chance of receiving the HD gene.

People who undergo gene testing and discover that they have an allele which falls into the intermediate category are presented with some concerns. On the one hand, they have been reassured about their own status, but they continue to have uncertainty about children they may have or are planning. A major question is what is the likelihood of the CAG repeats expanding and causing Huntington's Disease in a child

More research needs to be done to answer this question but several factors which affect likelihood are known at this time. One factor is the CAG count itself. The likelihood of expansion is greater with higher CAG counts. There has only been one known case of expansion from 27, the lower end of the range. A father with this count transmitted an allele with 38 CAG repeats to his child.

A second factor is gender. Expansions of CAG counts are more common when the parent is male, regardless of whether he is in the intermediate, reduced penetrance, or full penentrance range. There has not yet been a case reported where this has happened from a mother and the likelihood of this happening is considered to be much less. There have been cases of maternal expansion from the reduced penetrance range, however.

A third factor is age. In the cases where an intermediate allele was transmitted into the affected range, the father was older with an average age of 36.7.

A fourth factor is family history. The risk of transmitting an allele in the HD range is higher if the person is from a family with new mutations rather than someone who has an intermediate allele from the 'general population.'

This requires some explanation. There is no routine screening for the HD gene and people who are not from HD families do not request the test unless they are showing Huntington's Disease-like symptoms, so the presence of intermediate alleles usually comes to light when someone who is at risk is testing. They may discover that they did not inherit their affected parent's HD gene but did inherit an intermediate allele from their other parent who is from a family where HD has not occurred. For the purposes of discussion, the authors call them GP:IAs (for general population intermediate alleles).

When someone without a family history is diagnosed with Huntington's Disease and the HD gene is confirmed through testing, siblings and parents may also seek testing to discover their own status. The transmitting parent with the intermediate allele or the siblings who have received an intermediate allele would be classified as part of a family with new mutations - NM:IA.

Why would there be a difference? The answer probably lies in haplotypes, or the actual coding of the whole gene. There are other variations in the coding of the huntingtin's gene that affect the likelihood of expansion. For example, the CAG repeats are usually followed by a CAA codon. But in two families identified so far, there's a point mutation and the CAA has been replaced by another CAG repeat. This makes the CAG repeats more likely to expand. There are other haplotypes which make expansion more likely. If there has already been one expansion in a family from an intermediate allele, the chances are greater that one of these haplotypes is found in the family.

So what are the person with an intermediate allele's actual chances of passing on a gene in the HD range to a child? The best estimate at this time comes from analysis of sperm. The likelihood of an intermediate CAG count expanding to the HD range (36 and above) in a child is estimated at 6 - 10 percent if the parent is male with a CAG count of 35, 6 percent if it's a GP:IA and ten if it's a NM:IA (Chong et al., 1997). The odds for women aren't known but are thought to be much less.

REFERENCE:

Chong, S.S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., Goldberg, Y.P., Haddad, B.R., Richards, F., Sillence, D., Greenberg, C.R., Ives, E., Van den Engh, G., Hughes, M.R., and Hayden, M.R. (1997). Contribution of DNA sequence and CAG size to mutation frquences of intermediate alleles for Huntington Disease: Evidence from single sperm analyses. Human Molecular Genetics 6:302-309.

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

Semaka, S Creighton, S Warby and MR Hayden

Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed.

Clinical Genetics Volume 70 October 2006, pp. 283-294