Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease

The risk of a person having a child with an inherited disorder, caused by a n unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the bi ological nature of the mutation and to the person's relation to the carrier of the full mutation. Once the mutation causing HD was identified, we were able to diagnose sporadic patients. A sporadic patient can sometimes be co nnected to a known HD pedigree by using a roster. By haplotyping and calcul ating the posterior identity-by-descent probability, we could establish whe ther a connection was coincidental or not. Furthermore, we describe the fre quency of intermediate and reduced penetrance alleles detected. Using the f amily history and the roster to search for a connection, we examined whethe r these alleles were on the HD haplotype of a family. It is important to kn ow the origin of an intermediate or reduced penetrance allele because if it comes from an HD branch of the family or from the non-HD affected side of the pedigree, different risks for relatives and penetrance ensue. In our st udy, most intermediate alleles came from the non-HD-affected side of the pe digree and had a repeat size in the lower range with a negligible risk for expansion. Intermediate alleles on the HD haplotypes were larger and found in predictive test applicants from known families or relatives from new mut ations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicant s from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplo typing in persons with intermediate and reduced penetrance alleles are esse ntial in considering the risk of a person having (a child with) HD. (C) 200 1 Wiley-Liss, Inc.