The Genetics of Huntington's Disease

A Basic Overview of the Genetic Process

basic genetic process

Vocabulary

  • Cells

    • Make up our body

  • Chromosomes

    • Each chromosome contains DNA​

  • DNA

    • The "instruction manual" that tells our cells what to do

  • Gene

    • A gene is a segment of DNA that codes for a specific protein

    • Genes are read by our body like a sentence or recipe

  • Genetic variant (mutation)

    o A difference or abnormality within a gene

    o A gene variant (mutation) is like a "typo" in the recipe book

  •  Repeat expansion 

o A type of genetic mutation

 

Huntington's disease (HD) is a genetic disease, which means it is passed down through generations. However, up to 10% of people with HD are unaware of a family history of HD, or may be the first in their family to be diagnosed with HD.

We have two copies of each gene because we inherit one copy from our biological mother and one copy from our biological father. HD is caused by a specific type of genetic variant (mutation) called a repeat expansion. Each person has two different numbers of CAG repeats, one on each copy of their gene HTT. HD is caused by having an abnormal number of CAG repeats within one copy of the gene HTT (ie, too many repeats).

The genetic variant (mutation) that's responsible for HD is inherited in an autosomal dominant manner. Therefore, only one copy of the genetic variant (abnormal number of CAG repeats) is necessary for an individual to have symptoms or risk for HD. Each child of an individual with HD has a 50% chance of inheriting the genetic variant (abnormal number of CAG repeats) from their affected parent. Autosomal dominant conditions are "passed down" to men and women equally, and do not skip generations, though there can be variability.

 

The Specifics of the Genetics of Huntington's​

What gene is responsible for HD?

Mutations in the HTT gene are responsible for Huntington's disease. This gene codes for the huntingtin protein and within the HTT gene is a DNA sequence known as the CAG trinucleotide repeat.​

What is the relationship between the number of CAG repeats and HD?

Everyone has this CAG sequence, but the number of times it is repeated varies. There is a range of values that indicate a person’s risk for HD.

· A repeat value of 26 or less on both copies of the gene is considered normal.

· A repeat value of 27-35 on one of the copies is considered normal but unstable, as the repeat length has the ability to lengthen.

o While this is not associated with symptoms of HD, an individual with these repeat values has the potential to have a child with a higher repeat length. Other family members may also have a risk to have a higher repeat length.

· A repeat value of 36-39 on one of the copies is an abnormal result, also called the reduced penetrance range.

o This means an individual may or may not develop HD symptoms in their lifetime, or may develop symptoms at a later age. A diagnosis of HD is based on the genetic test result AND whether there are symptoms present.

· A repeat value of 40 or above on one of the copies is an abnormal result, also called a fully penetrant result.

o This means an individual has HD, or will develop HD in their lifetime. A diagnosis of HD is based on the genetic test result AND whether there are symptoms present.

 

 

These topics can be reviewed in more detail during a visit with a genetic counselor. Click here (https://www.med.upenn.edu/pennhdcenter/genetic-counseling.html ) for more information about genetic counseling.