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Genetic Family Testing for an X-linked Recessive Diseases

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What is an X-linked recessive disease?
An X-linked recessive disease is an inherited disease that typically is seen only in males. Females may "carry" the disease, but are usually not affected. An X-linked recessive disease may "skip" generations, carried by females. Approximately half of the sons of a carrier mother will be affected by the disease, and approximately half of the daughters of a carrier mother will also be carriers. All daughters of an affected male will be carriers of the disease. However, sons can never inherit an X-linked disease from their father.

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The meaning of X-linked
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 X-linked recessive inheritance
X-linked recessive diseases only develop if a disease-associated genetic variation is present on all available copies of the X chromosome. In females, presence of a disease-associated genetic variation only on the X chromosome inherited from the mother or only on the X chromosome inherited from the father is usually not sufficient to cause disease. In males, in contrast, presence of a disease-associated genetic variation on the single X chromosome inherited from the mother is sufficient to cause disease. The characteristic features of X-linked recessive inheritance are that the disease is seen almost exclusively in males and that it can never be passed from father to son, since fathers give their Y chromosome, not their X chromosome, to their sons.

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Why should family members of patients with an X-linked recessive disease be tested for that disease?
The sisters of a patient with an X-linked recessive disease have, on average, a 50% chance of harboring the same disease-associated genetic variation as the patient and thus being carriers of the disease. The patient’s daughters are certain to be carriers of the disease. The patient’s mother is also certain to be a carrier of the disease, unless the genetic variation first appeared in the patient. Every carrier female in an affected family has a 50% chance of having an affected son. Once the familial mutation associated with the disease is known, genetic family testing can identify who among female family members carries the disease and who doesn’t. If the familial mutation is not present, a female family member can be reassured that her sons are not at any greater risk of the disease than the general population. If the familial mutation is present, the female family member knows that her sons are a greatly increased risk of the disease and that she and her sons’ physicians have to be vigilant for symptoms of the disease and consider 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 carriers of disease-associated genetic variations, since carriers typically do not show any symptoms.

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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 X-linked recessive inheritance, the ideal testing sequence is illustrated in Figures 1A and B below. The same hypothetical family tree is shown two times. The male index patient is indicated by the arrow. His daughters are "obligate carriers" of the familial mutation, ie, they are certain to harbor the familial mutation. In the first round of genetic family testing (Figure 1A), the mother and the siblings of the index patient are tested for presence of the familial mutation. The father of the index patient does not need to be tested, because the index patient is male and therefore cannot have inherited the X-linked familial mutation from his father. In the example shown here, the mother and the sister harbor the familial mutation, while the brother does not. In the second round of genetic testing (Figure 1B), the children of the affected sister (ie, the niece and nephew of the index patient) and the sister of the affected parent (the maternal aunt of the index patient) are tested. The nephew harbors the familial mutation, the niece does not. The paternal aunt also harbors 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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The meaning of skewed X-inactivation
While females harbor two copies of the X chromosome, only one copy is "active." The other copy becomes permanently inactivated during development. Usually, this "X inactivation" is a random process: In some cells, the X chromosome inherited from the mother will be inactivated; in other cells, the X chromosome inherited from the father will be inactivated. Skewed X-inactivation is present when either the maternal or the paternal copy of the X chromosome is preferentially inactivated. If one copy of the X chromosome harbors a disease-associated genetic variation and the other does not, skewing of X-inactivation towards the unaffected chromosome copy can lead to X-linked recessive disease in females. On the other hand, skewing of X inactivation towards the affected chromosome copy can prevent even mild disease symptoms in females.

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