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 an unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the biological 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 connected to a known HD pedigree by using a roster. By haplotyping and calculating the posterior identity-by-descent probability, we could establish whether a connection was coincidental or not. Furthermore, we describe the frequency of intermediate and reduced penetrance alleles detected. Using the family history and the roster to search for a connection, we examined whether these alleles were on the HD haplotype of a family. It is important to know 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 study, most intermediate alleles came from the non-HD-affected side of the pedigree 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 mutations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicants from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplotyping in persons with intermediate and reduced penetrance alleles are essential in considering the risk of a person having (a child with) HD.
Maat-Kievit
A
A
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. maat@kgen.azr.nl
Helderman-van den Enden
P
P
Losekoot
M
M
de Knijff
P
P
Belfroid
R
R
Vegter-van der Vlis
M
M
Roos
R
R
Breuning
M
M
D017668:Age of Onset; D000483:Alleles; D004247:DNA / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D012042:Registries; D012306:Risk; D018911:Trinucleotide Repeats / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D004247:DNA