An intergenerational contraction of a fully penetrant Huntington disease allele to a reduced penetrance allele: interpretation of results and significance for risk assessment and genetic counseling

Am J Med Genet A. 2009 Feb 15;149A(4):732-6. doi: 10.1002/ajmg.a.32720.

Abstract

We report on a healthy 50-year-old woman who sought predictive testing due to a family history of Huntington disease (HD). Her 73-year-old mother had recently been confirmed to carry an HD allele of 42 CAG repeats, and started to show symptoms of HD at age 68. Clinically diagnosed HD is present in the maternal grandfather, maternal uncle, and three maternal cousins. Molecular analysis of the HD CAG repeat region identified an allele with 38 CAG repeats in the consultand, giving evidence of allele size contraction from the maternal 42 CAG repeat allele. Mitotic stability of the CAG repeat was demonstrated in DNA from a skin sample with the same allele size (38). In addition to sex of the parent and size of the repeat, recent data analysis of intergenerational stability of the CAG repeat size suggest a gender effect of the offspring on the likelihood of allele contraction or expansion. Discussion of these results with this patient presented challenges in providing appropriate risk assessment for developing the disease herself as well as the future risk to her offspring.

Publication types

  • Case Reports

MeSH terms

  • Age of Onset
  • Aged
  • Alleles
  • Anticipation, Genetic
  • Base Sequence
  • DNA Primers / genetics
  • Female
  • Genetic Counseling / psychology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / diagnosis
  • Huntington Disease / genetics*
  • Huntington Disease / psychology
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Pedigree
  • Penetrance*
  • Polymerase Chain Reaction
  • Risk Factors
  • Trinucleotide Repeat Expansion*

Substances

  • DNA Primers
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins