FIRST GENE DIRECTLY LINKED TO WILLIAMS SYNDROME

A Scientific Explanation For WS Families
(Written in 1993)

by
*Howard M. Lenhoff, Executive Vice President
Williams Syndrome Foundation, and
Professor of Developmental and Cell Biology
University of California, Irvine

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The discovery - a loss of the gene for elastin through a microdeletion of chromosome seven: Dr. Colleen Morris and her collaborators have shown conclusively that nearly all [people with Williams Syndrome] tested lack the gene for elastin in one of their two chromosomes called "chromosome Number 7," whereas the normal parents possess both copies of the gene. Every non-Williams person has two chromosome Number 7s, having received one from each parent. Technically speaking, the absence of a gene or of any small segment of a chromosome is called a microdeletion. One of the genes removed in the microdeletion of chromosome Number 7 in WS individuals is the gene controlling the synthesis of elastin, a protein important in the functioning of contractile tissues, such as those found in the heart and arteries (see related questions and answers about elastin).
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Is a microdeletion a mutation? No, not in the strict sense. A gene is the particular segment of a long chain of DNA (deoxyribonucleic acid) which provides information for the cell to make a specific protein, such as hemoglobin or elastin. The DNA chain is made up of a specific arrangement of four smaller molecules, called A, G, T, and C for short, that are linked together. A mutation occurs when some foreign agent, such as radiation, causes a permanent change in one of the A, G, T, or C molecules. In contrast, a microdeletion occurs when a gene or a small number of genes are removed from a chromosome.
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Where does the microdeletion originate? The microdeletion must originate in either the egg or sperm provided by the parents which unite to form the fertilized egg giving rise to the Williams syndrome child. We can conclude that nothing could have happened during the gestation of the Williams child that could have contributed to the establishment of that microdeletion. Williams syndrome is established at conception, and not thereafter.
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What are the chances of a family having two children with Williams syndrome? Extremely rare, except in the case of identical twins.
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What are the chances of a brother or sister of a Williams individual having a child with Williams syndrome? Also extremely rare, with no greater a chance than individuals from the general population.
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Can the microdeletion be passed on from a Williams syndrome individual who parents a child? Yes. There is a 50/50 chance that a Williams parent can pass on the chromosome with the microdeletion to its offspring because the Williams syndrome parent has two chromosomes Number 7, one with the microdeletion, and one without it. Either one of the two chromosomes of the Williams parent will appear in the gamete (i.e. egg or sperm) which eventually forms the child. If it is the chromosome with the microdeletion, then the child will also be a Williams child. If it is the chromosome without the microdeletion, then the child will not be a Williams child. It is strictly a matter of chance whether or not the Williams parent passes on the chromosome 7 with the microdeletion to her or his offspring.
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Will this discovery allow for the early diagnosis of Williams syndrome? Yes. Because it is possible to mark with a fluorescent dye the complete Number 7 chromosome (the one without the microdeletion) and not the defective Number 7 chromosome (the one having the microdeletion), it is possible to analyze the cells of the early embryo removed by the processes of amniocentesis or chorionic villi analysis, or to analyze cells of a WS child at any age. Perhaps the most useful aspect of such early diagnoses is that it will now be possible to use this chromosomal test as a near conclusive diagnostic indicator of WS when evaluations of other characteristics of the syndrome are in doubt. Nonetheless, there still remains the possibility that there will be a small percentage of individuals with Williams syndrome who will not show this microdeletion.
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Does the discovery of the microdeletion of the elastin gene in Williams syndrome individuals explain all of the characteristics of Williams syndrome? Not completely. The microdeletion of the elastin gene can help explain the: facial features; low voice; diverticulosis (formation of a sac or pouch) of the bladder and colon; and heart, hernia, and joint problems present in Williams syndrome individuals. Why? Because sufficient amounts of the protein elastin are needed for normal functioning of the heart, aorta, and other contractile tissues and organs. It is particularly interesting to note that WS individuals both with and without heart problems show the microdeletion of the elastin gene.
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What are some questions that need to be answered? It is not clear at this time, for example, how the absence of an elastin gene would lead to hypercalcaemia, mental retardation, musical ability, and other features of Williams syndrome. One possibility which needs to be explored suggests that the gene or genes affecting those other traits may be close to the elastin gene, and because of the closeness also may be eliminated in the microdeletion. It is also possible that the microdeletions in chromosome Number 7 of WS individuals may differ in size, with varying numbers of other genes missing, thereby accounting for individuals who have some of the WS symptoms, but who are still hard to diagnose with certainty. Such possible variation in the size of the microdeletion may account for some of the variability in the symptoms of WS seen in different individuals.
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Thus, although we are now much closer to understanding the genetic basis of Williams syndrome, there is still additional genetic research that needs to be done. The path, however, now looks shorter and clearer because of the pioneering work of Dr. Morris and her colleagues.