Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications.

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.

Factors associated with HD CAG repeat instability in Huntington disease.

BACKGROUND: The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene. RESULTS: In this study, we used a collection of 112 sperm DNAs from male HD gene-positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat-length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father-offspring and 311 mother-offspring pairs in this Venezuelan pedigree. Repeat-length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat-length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring. CONCLUSION: Significant sibling-sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.

Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds.

BACKGROUND: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations. OBJECTIVE: To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela. METHODS: Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B). RESULTS: The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes. CONCLUSIONS: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.

Software support for Huntingtons disease research.

Huntingtons disease (HD) is a hereditary disorder involving the central nervous system. Its effects are devastating, to the affected person as well as his family. The Department of Medical and Molecular Genetics at Indiana University (IU) plays an integral part in Huntingtons research by providing computerized repositories of HD family information for researchers and families. The National Huntingtons Disease Research Roster, founded in 1979 at IU, and the Huntingtons Disease in Venezuela Project database contain information that has proven to be invaluable in the worldwide field of HD research. This paper addresses the types of information stored in each database, the pedigree database program (MEGADATS) used to manage the data, and significant findings that have resulted from access to the data.