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Genetic Family Testing for an Autosomal Dominant Disease

 

 

What is an autosomal dominant disease?
An autosomal dominant disease is an inherited disease that typically is seen in every generation of an affected family. Autosomal diseases usually affect males and females equally. Affected parents will pass an autosomal dominant disease to, on average, half of their daughters and half of their sons.

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The meaning of autosomal
Human genes are organized into 23 separate "packages," called chromosomes. All somatic cells within the human body, that is, all cells except for egg cells in females and sperm cells in males, contain two copies of each of the 23 chromosomes. Chromosomes 1 through 22 are called autosomes, and the genes located on them are known as autosomal genes. Both females and males inherit one copy of each autosome from the mother and the other copy from the father. Chromosome 23, called the sex chromosome, occurs in 2 forms, the X chromosome and the Y chromosome. Females have two copies of the X chromosome, one inherited from the mother and the other from the father. Males have one copy of the X chromosome and one copy of the Y chromosome. Males inherit the X chromosome from their mother and the Y chromosome from their father. Genes located on the X and Y chromosomes are called X-linked and Y-linked, respectively.

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The meaning of dominant inheritance
Dominant diseases can develop as soon as a disease-associated genetic variation is present on one of the two copies of a given autosomal chromosome. In other words, presence of a disease-associated genetic variation only on the chromosome copy inherited from the mother or only on the chromosome copy inherited from the father is sufficient to cause disease. Dominantly inherited diseases typically do not skip generations, since the disease is passed with the genetic variation from a parent to a child.

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Why should family members of patients with an autosomal dominant disease be tested for that disease?
The children, siblings, and parents of a patient with an autosomal dominant disease each have a 50% chance of harboring the same disease-associated variation as the patient and thus being affected by the same disease. Once the familial mutation associated with the disease is known, genetic family testing can identify both at-risk and not-at-risk family members. If the familial mutation is not present, the family member can be reassured that he or she and his or her descendants are not at any greater risk of the disease than the general population. If the familial mutation is present, the family member and his or her parents, siblings, and children are at greatly increased risk for the disease. Family members harboring the familial mutation know that they and their physicians have to be vigilant for symptoms of the disease and seek treatment as soon as symptoms appear.

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Why is genetic testing better than other diagnostic methods for family testing?
Genetic testing is often the best tool for identifying both at-risk and not-at-risk family members. For example, a family member without any symptoms of the disease may be unaffected, or he or she may be presymptomatic – that is, he or she may simply not have developed symptoms of the disease yet. Sometimes, symptoms may be present, but it may be unclear if they are due to the disease in question or due to unrelated reasons. It may also be possible that an individual harboring the familial mutation never develops symptoms (this is known as "low penetrance" of the disease). However, this individual can still pass on the mutation to his or her children, who may then develop the disease. Genetic testing can determine if a family member harbors the familial mutation or not. A family member harboring the familial mutation is at increased risk of the disease, a family member not harboring the familial mutation is not at increased risk of the disease.

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Who in the patient’s family should be tested?
Ideally, family testing should "radiate" outward from the index patient (the patient in whom the familial mutation was initially identified). For a disease with autosomal dominant inheritance, the ideal testing sequence is illustrated in Figures 1A and 1B below. The same hypothetical family tree is shown two times. The index patient is indicated by the arrow. In the first round of genetic family testing (Figure 1A), the children, siblings, and parents of the index patient are tested for presence of the familial mutation. In the example shown here, the father, the son, and one brother harbor the familial mutation, while the mother, the daughter, and the other brother do not harbor the familial mutation. In the second round of genetic testing (Figure 1B), the children of the affected brother (ie, the nieces of the index patient) and the sister of the affected parent (the paternal aunt of the index patient) are tested. Two of the three nieces carry the familial mutation, one does not. The paternal aunt also carries the familial mutation, and her children, the cousins of the index patient, should be tested next. Note that only blood relatives of the index patient need to be tested! Relatives by marriage or adoption are not at risk of harboring the familial mutation found in the index patient.

Figure 1A: 1st round of genetic family testing

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Figure 1B: 2nd round of genetic family testing

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The meaning of mosaicism
Mosaicism means that a certain genetic variation does not occur in all cells of the body, but only in some. In other words, an individual can be a "mosaic" of cells that harbor the genetic variation and cells that do not harbor the genetic variation. Genetic testing may or may not be able to detect a genetic variation in a mosaic individual, depending on how many cells and which cells harbor the genetic variation. The risk of inheriting a disease-associated genetic variation from a mosaic individual varies widely and cannot be predicted.

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The meaning of "de novo" genetic variation
Sometime, a disease-associated genetic variation is newly generated in an individual. In other words, an inherited disease can suddenly appear within a member of a previously unaffected family. The descendants of the affected family member are then at high risk of inheriting the newly generated familial mutation. In addition, the siblings of the affected family member may also be at increased risk of the disease, since the familial mutation may, in fact, have been generated in one of the patient’s parents – ie, one of the parents could be a mosaic for the genetic variation. It is therefore important to consider genetic testing of the index patient’s siblings even if the genetic variation found in the index patient cannot be detected in either parent.

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