Clinical Utility of Direct Mutation Testing for Congenital Nephrogenic Diabetes Insipidus in Families
|Title:||Clinical Utility of Direct Mutation Testing for Congenital Nephrogenic Diabetes Insipidus in Families|
|Authors:||Wildin, Robert; Cogdell, David E.|
|Date Published:||March 01, 1999|
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Researchers have discovered that mutations in either the vasopressin-2 receptor (AVPR2) gene or the aquaporin-2 (AQP2) gene can result in NDI. NDI-causing mutations of the AVPR2 gene, which is located on the X chromosome, are far more prevalent than NDI-causing mutations of the AQP2 gene, which is located on chromosome 12, an autosomal gene.
Whether caused by mutated AVPR2 or AQP2 genes, the symptoms are identical. The former mutation is inherited in an X-linked fashion, and the latter is inherited in an autosomal recessive, and extremely rarely, in an autosomal dominant fashion.
Hereditary NDI can be clinically diagnosed by observing inheritance patterns if the disease has affected other family members, by measuring the urine and blood for specific variables, and by subjecting the patient to a short, carefully monitored water-fast, then injecting him or her with dDAVP, a synthetically modified form of AVP. These diagnostic measures are effective, though expensive and somewhat invasive (frequent blood draws, urine samples and water restriction). Another form of diagnosis entails testing suspect genes for mutations.
In this article, Wildin and Cogdell reviewed NDI cases which had been referred to their laboratories and selected 5 cases that illustrate the breadth and value of direct genetic testing for mutations of the AVPR2 gene in cases of NDI. These cases illustrate how genetic testing was beneficially used:
- It confirmed a clinical diagnosis of NDI in a boy whose family history showed no presence of NDI. The boy was found to have a mutated AVPR2 gene, and his mother, also tested, was found to be a carrier. A large fraction of new NDI cases have no previous history of NDI. Thus, genetic testing can confirm a spontaneously occurring mutation that can then be inherited.
- Genetic testing was able to confirm a clinical diagnosis of NDI in an affected girl. Generally, males inherit NDI from their mothers and display the full symptoms of the disease. Females can carry the mutated gene responsible for NDI, but show no or mild symptoms. Occasionally, females do express severe symptoms because a number of their X chromosomes carrying the healthy AVPR2 gene (their other X chromosome carries the mutated AVPR2 gene) are inactivated.
- Once an NDI case is identified, female relatives can be tested to see if they carry the mutated AVPR2 gene. If they do have it, they are NDI carriers and have a probability of passing it on. Knowing this can help a woman prepare for proper care of her baby should the baby be born with NDI.
- If a family has a history of NDI, the newborn can be immediately tested for the presence of an NDI gene by drawing a sample of the newborn's cord blood. If the test reveals a mutated AVPR2 gene, the newborn can receive immediate treatment.
- Genetic testing can establish the nature of the inheritance pattern: i.e. whether it is X-linked recessive, autosomal recessive, or autosomal dominant.
The authors conclude that direct mutation analysis in patients suspected of NDI and in selective family members of the patient can be of great benefit in producing clear, unambiguous diagnoses. Of the different methods of genetic testing, the authors conclude that automatic sequencing is the preferred method.