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Molecular Cytogenetics (FISH) Vol. 13: Spring, 1996

Doing my clinical cytogenetics fellowship at the University of Utah brought several pleasures. The following narrative summarizes the highlights of the endeavor. My experience with FISH was somewhat limited before coming to Dr. Brothman's laboratory. Little did I know upon arriving in Utah in June, 1993 that FISH (and one particular microdeletion syndrome) would become a central part of my career.

Background

Williams syndrome (WS) is a multisystem disorder characterized by growth and developmental delays, characteristic facies and personality, supravalvar aortic stenosis, and occasionally idiopathic infantile hypercalcemia. WS usually occurs sporadically, though autosomal dominant inheritance has been reported. Variable expression of the phenotype may complicate diagnosis in some patients. Supravalvar aortic stenosis (SVAS), which can also be an isolated autosomal dominant trait, is frequently associated with WS. SVAS is an inherited vascular disease caused by mutations in the elastin gene (ELN).

Previous studies have identified linkage between the elastin gene and SVAS in two families with the location of the gene found, by FISH, to be on chromosome 7 at q11.23. Most of the SVAS work was done by Dr. Mark Keating's group, which had been working closely with Colleen Morris, M.D., a clinical geneticist from the University of Nevada (who, incidentally did her fellowship at Utah). These two groups had found that many patients with Williams syndrome showed defects in a major component of connective tissue, elastin. Further investigations of SVAS and WS suggested that WS is a contiguous gene disorder in which connective-tissue and vascular abnormalities are caused by the deletion of one elastin allele at the 7q11.23 site.

Dr. Keating visited our weekly Genetics Rounds and it was decided that we would pursue testing of all lymphoblastoid cell lines established from patients referred to Dr. Keatings lab through the Williams syndrome Association (WSA). I tested over 300 patients over the next several months. Correlation with clinical information came with the assistance of Dr. Morris, who had thoroughly reviewed the clinical features of all persons referred for testing.

Results

Molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the WSA, plus 40 clinical cytogenetics cases referred by primary-care physicians. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results supported the usefulness of FISH for the detection of elastin deletions as an initial diagnostic test for WS.

Hence, the discovery of the role of elastin in WS led to the development of a potential laboratory test for the condition. Although our data show that no detectable cytogenetic abnormality has been found in WS patients, we still believe that classical cytogenetic analysis with FISH is the most thorough approach to evaluation of these patients. However, we also believe that metaphase FISH alone is likely to provide a high-yield diagnostic test for WS. If no deletion is seen by FISH, it is imperative that routine cytogenetic studies be performed. Likewise, if a deletion is detected in a child, we suggest parental studies (at least metaphase FISH) to ensure that no rearrangement involving ELN is present.

Conclusion

We believe that FISH studies showing loss of the elastin region, as an initial laboratory evaluation for WS, provides an accurate means of diagnosing the syndrome. Our finding of 38% deletions by FISH in the clinical cytogenetics cases is intriguing and represents one of the highest-yield cytogenetic tests available. Since many of these patients were referred without the stringent evaluation of a medical geneticist experienced in the diagnosis of WS, it is anticipated with FISH will provide help in the diagnosis of patients who can then be referred for genetic workup and, ultimately, improved health care. I anticipate that further research will elucidate more precise mechanisms involved in this contiguous gene syndrome.

Contributed by Mary C. Lowery, Ph.D. (CO)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Regional Genetic Services Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table Of Contents: Molecular Cytogenetics (FISH)
Introduction & Basic Techniques
Applications of FISH Technology
FISH Applications in Cancer Cytogenetics
FISH in Microdeletion Syndromes
FISHing in Unknown Waters
Regulatory Issues and FISH

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