Huntington’s disease’s inheritance pattern is autosomal dominant.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Risk estimation

 

Parents of an affected individual

 

In most cases, patients have an affected parent. Death of the parent before the diagnosis of the disease, carrying intermediate alleles, not diagnosing properly other family members or late symptom onset might result in negative family history. Molecular testing of parents should be performed in order to refuse a de novo mutation.

 

Siblings of an affected individual

 

The risk depends on the CAG repeat expansion their parents carry.

 

• Parent carrying HD causing allele (p.Gln18(>40)): The risk to the siblings of inheriting the mutated allele is 50 %.

 

• Parent carrying Intermediate allele (p.Gln18(27_35)): The progeny of a male carrier of the permutation can inherit the mutation due to the expansion during spermatogenesis and the risk to the siblings becomes 5 %. If the allele inherited by the sibling is a reduced penetrance HD causing allele they might not develop the pathologic phenotype. 

 

Progeny of an affected individual

 

The risk of inheriting the HD causing allele is 50 % should the proband be heterozygous. Children of an affected homozygous individual have 100 % of risk of being affected. Intermediate alleles represent a risk for the progeny but not for the carrier who is asymptomatic.

The risk degree depends on:

 

• CAG repeat expansion: larger sized alleles relay higher risk since they are more likely to expansion.

 

• Age and gender of the progenitors: A male carrying an intermediate allele might transmit this allele to offspring and during spermatogenesis it can become expanded. The likelihood of a maternal transmission of an expanded allele from an intermediate allele is considered very small. It could be assumed that the probability of expansion in offspring is equivalent to the probability of a male intermediate carrier has affected progeny. The risk of expanded penetrant allele has been estimated as 1/6241 to 1/951. Advanced age also increases the risk. (Hendricks et al, 2009).

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• Stability of CAG repeats: Presence of CCG repeats interrupting CAG repeats become more stable. Predictive testing should be performed for those individuals at risk who tested asymptomatic to determine the diagnosis. This test does not estimate severity and age of onset. Before testing individuals an informed consent should be signed. The aims of performing this test in asymptomatic at-risk individuals are providing reproductive and financial solutions and career planning in order to face their new future when positive results are obtained. These individuals should be assessed about healthy lifestyle, disability insurance, future interactions with society and discrimination. Only adults can be tested because of ethical considerations. At the age of eighteen decision on whether the test should be performed in individuals at risk is to recommend. In case of de novo mutations, adoption and alternate paternity and maternity should be taken into consideration.

 

 

Preimplantational genetic diagnosis

 

It could be performed in case of having identified the Huntington’s disease allele in parents or in members of the family. This technique is used to analyse in vitro embryos at-risk of developing the disease.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Prenatal diagnosis

 

Prenatal testing in amniotic fluid cells (by extracting fetal cells from 15 weeks stage fetus) and chorionic villus samples (by extracting fetal cells from 10 weeks stage fetus) should be carried out in case of 50 % risk pregnancies. Depending on the country, pregnancy interruption could be considered.