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Marfan Syndrome Book excerpt
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THE ROLE OF HEREDITY AND FAMILY HISTORY
Excerpt from the NMF booklet The Marfan Syndrome, by Reed E. Pyeritz, M.D., Ph.D. and Cheryll Gasner, M.N., C./F.N.P. Fifth Edition, July, 1999, Revised September 2001
Genetics
A gene is the fundamental unit of heredity; humans have 50-100 thousand of them, each composed of DNA and organized along the chromosomes. Most genes occur in pairs. One member of each pair is passed (inherited) from the mother and one from the father. Most genes contain the instructions (encode) for the cell to make specific proteins.
In anyone affected by the Marfan syndrome, the gene that causes the Marfan syndrome either may be inherited from a parent also affected by the condition or from an unaffected parent who has had a change (mutation) in his sperm or her egg. About two-thirds to three-quarters of all people with the Marfan syndrome inherited their mutant gene from a parent who has the condition. This means that about one-quarter to one-third of affected people had two unaffected parents, and that they developed the Marfan syndrome because of a new mutation. New mutations occur spontaneously and frequently in the DNA in the eggs (oocytes) and sperm of every adult; it is just by chance that the mutation occurs in the gene that causes the Marfan syndrome.
How the Marfan Syndrome Is Passed in Families
Males and females are affected by the Marfan syndrome equally and, on average, with similar severity. The condition occurs in successive generations, because each child of an affected parent has a fifty-fifty chance of inheriting the Marfan syndrome gene, regardless of whether the affected parent is a man or a woman. Only one parent need be affected. In about 1/4 to 1/3 of all cases of the Marfan syndrome, neither parent is affected; the condition arises in the affected individual because of a spontaneous mutation in the gene that causes Marfan syndrome in the sperm or the egg of one of the unaffected parents. In such families, the age of the father is often greater than that of fathers in the general population, suggesting that the spontaneous mutation occurs most often in the cells of the testes, the male reproductive organ that produces sperm. Mutations occur in the germ cells constantly; mutations that cause the Marfan syndrome arise quite infrequently, about once every 20,000 births. When neither parent of a child with teh Marfan syndrome is affected, their risk of having another child with the Marfan syndrome is generally about 1 in 20,000.in that range.
Figure 11. The pedigree diagram of a family in which the Marfan syndrome occurs. Squares indicate men and circles women. An open symbol signifies the person does not show any signs of the Marfan syndrome, while the shaded symbol indicates that the Marfan syndrome is present. In generation I, neither parent is affected, so that the affected man in generation II most likely received his "Marfan gene" as a result of a new mutation in either his mother’s egg or his father's sperm. On average, each of the offspring (generation III) of this affected individual had a 50-50 chance of inheriting the Marfan syndrome. When an individual does not inherit the "Marfan gene," he or she has no chance of passing it on to future generations.
Although the range of severity of the condition (variable expression) can be exceedingly wide among affected relatives, few, if any, people have the Marfan gene but fail to show some outward evidence of it. There are, therefore, almost no "skipped generations." If a relative of someone with the Marfan syndrome shows no sign whatever of the condition, then the relative is extremely unlikely to have inherited the mutant gene, and therefore equally unlikely to have a child with the Marfan syndrome.
All of these characteristics are distinctive of a specific type of inheritance, called autosomal dominant. "Autosomal" refers to the fact that the Marfan gene does not occur on one of the sex chromosomes. "Dominant" means that only one copy of the pair of genes needs to carry the Marfan mutation for the condition to be present. The alternate form of inheritance is recessive, in which both parents must carry a copy of the mutant gene, as in sickle cell disease and cystic fibrosis. Other examples of autosomal dominant conditions are familial hypercholesterolemia (one of the causes of severe elevation of blood cholesterol), neurofibromatosis, several conditions that cause multiple polyps in the large bowel and predispose to cancer, and many of the other heritable disorders of connective tissue. Over 3000 separate conditions and traits are known to be inherited in an autosomal dominant pattern.
Your Family Tree
It is useful for any family to keep track of all pregnancies and their outcomes, the health and medical problems or relatives, and the age at which relatives die and the causes of death. Often one relative takes on this role of "family historian," and this individual can be especially helpful when a person needs to gather information to present to their physician. A complete evaluation for the Marfan syndrome must involve careful inspection of the family history. It can save considerable time if the available data are retrieved before the appointment, although invariably additional questions are raised (especially by genetics specialists!) that require more research into the family tree. There is often a fine line between working with relatives in a constructive way, and prying into personal issues that are quite emotional. A genetic counselor can suggest ways of dealing with situations where confidentiality and self-interest clash.
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