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.
Publisher: Pediatrics
Date Published: March 01, 1999
Reference Number: 225
Objective. To ascertain the clinical scenarios in which genetic testing for congenital nephrogenic diabetes insipidus (NDI) by direct detection of mutations might prove valuable, and to assess the use of automated sequencing for testing. Methods. We reviewed NDI cases referred to our research laboratory for enrollment in our study of mutations in the AVPR2 gene that is disrupted in the X-linked form of the disease. We selected 5 cases that illustrate the value of genetic testing in different clinical situations. Clinical information was obtained from the patient's personal physicians and the patients' families. Direct automated fluorescent DNA sequencing of AVPR2 gene amplification product was used to identify disease-associated mutations in patients. The presence or absence of mutations in family members was then established by using automated sequencing, restriction enzyme analysis, or both. Results. In 2 of the 5 selected cases, the diagnosis of a genetic form of NDI was confirmed by mutation analysis in a sporadic case of an affected boy. In 2 cases, a suspected diagnosis of X-linked NDI was confirmed in an affected girl. In 4 of the cases, 1 or more unaffected female relatives were determined to carry or not to carry the disease-associated gene. In 2 cases, testing of the newborn child of a known or suspected carrier confirmed the clinical suspicion of affected status and justified proactive therapy. In 4 of the 5 cases, the mode of inheritance was not clear from the family history and was established as X-linked by the testing. Assay for restriction sites changed by disease-associated mutations agreed with the automated sequencing results. Conclusions. We conclude that direct mutation analysis in patients suspected of NDI and in selected family members is indicated. The results of testing can confirm a clinical diagnosis of disease, which may otherwise be difficult to make in girls. It can further establish the mode of inheritance, unambiguously distinguish carriers from noncarriers, and justify special observation or treatment of newborns at risk, thereby averting dehydration and the attendant complications. We also conclude that, with proper controls, automated sequencing is the preferred method of testing, because it is sufficiently robust, sensitive, and adaptable for this short gene with a large variety of causative mutations.
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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)

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the kidneys' inability to respond to the antidiuretic hormone, arginine vasopressin (AVP). The two main symptoms of NDI are polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst). Symptoms of the disorder generally manifest in the first days of life, and if they go unrecognized and untreated, severe bouts of dehydration could occur which could cause brain damage, permanent mental retardation, and even death. Thus, it is important that NDI be recognized early and managed appropriately. The most important aspect of management is the provision of adequate amounts of water for the NDI infant to drink.

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.