Draft Genetic Test Review
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Cystic Fibrosis
Clinical Validity
(436KB)
CLINICAL VALIDITY
Question 18: How often is the test positive when the disorder is present?
Question 19: How often is the test negative when the disorder is not present?
Question 20: Are there methods to resolve clinical false positive results in a timely manner?
Question 21: What is the prevalence of the disorder in this setting?
Question 22: Has the test been adequately validated on all populations to which it may be offered?
Question 23: What are the positive and negative predictive values?
Question 24: What are the genotype/phenotype relationships?
Question 25: What are the genetic, environmental or other modifiers?
CLINICAL VALIDITY
Question 20: Are there methods to resolve false positive results in a timely manner?
| Summary
Clinical false positives occur when two mutations are found in the fetus, but the phenotype is not classic cystic fibrosis.
Three of the less common mutations in the recommended screening panel are often not associated with the classic phenotype
- R117H occurs about 20 times more often in the general population than expected. A well-defined protocol exists to identify clinical false positive results
- D1152H occurs about 100 times more often in the Ashkenazi Jewish population than expected. No method exists for resolving clinical false positive results.
- I148T occurs about 100 times more often in the general population than expected. No method exists for resolving clinical false positive results.
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One definition of a clinical false positive result would be a fetus with two of the mutations contained in the recommended panel that would not develop the phenotype generally associated with cystic fibrosis. Several of the less common mutations in the recommended panel are not associated with classic cystic fibrosis most of time. The best known of these is R117H. In the early 1990s it was recognized that too many R117H mutations were being identified in the general population, based on the known frequency of that mutation among affected individuals (Witt et al., 1992). Since then, it has been discovered that the chromosomal background is an important factor in the phenotypic expression of this mutation (Kiesewetter et al., 1993). Currently, a well described protocol exists (Grody et al., 2001) to identify those in whom the R117H mutation is likely to be associated with classic cystic fibrosis (when combined with another deleterious mutation). That protocol can also help to identify those likely to have offspring with other very mild or normal phenotypes (Question 24).
The I148T mutation is also found too often in the general population. This mutation is now known to exist in the compound heterozygous state in asymptomatic individuals. In one study (Rohlfs et al., 2001), five adult were identified with the delF508/I148T genotype who had been referred for prenatal screening; all were asymptomatic for cystic fibrosis. That same study reported that the I148T mutation accounted for 6.4 percent of 1,754 mutations identified among 42,784 individuals without cystic fibrosis (NB: This higher than expected rate has been confirmed by D Witt in a presentation to ASHG in 2001). This is in contrast to I148T being identified in 0.06 percent of the 9,236 chromosomes from individuals with cystic fibrosis (Rohlfs et al., 2001). The well described protocol that is useful in determining the phenotype associated with R117H (referred to above) was not helpful in determining phenotype for this mutation. Thus, it appears that 99 of 100 I148T mutations are not associated with disease. Currently, there is no method to resolve clinical false positives when the I148T mutations are present in the fetus.
Although the mutation D1152H is not in the recommended panel, it is included in several commercial products and will, therefore, be part of the testing panel used by some screening laboratories in the United States. D1152H is an infrequent finding among Jewish individuals with classic cystic fibrosis. In a comprehensive study of cystic fibrosis patients in Israel (Kerem et al., 1995), no D1152H mutations were identified among 261 chromosomes from Ashkenazi Jewish patients and two D1152H mutations were found among 105 chromosomes from non-Ashkenazi Jewish patients. When testing the general population of Ashkenazi Jewish individuals for carrier status (Orgad et al., 2001), one study found that 18 percent of all mutations identified were D1152H. Clearly, many of these mutations are not associated with classic cystic fibrosis, and the phenotype of a compound heterozygote with D1152H is likely to be normal. It is not yet clear whether over-representation of this mutation exists outside of the Jewish population.
Gap in Knowledge: Genotype/Phenotype Relationships in I148T or D1152H Compound Heterozygotes.
These two mutations are found in carrier individuals much more often than expected and are, therefore, most often associated with a normal phenotype. Currently, however, it is not possible to predict the phenotype in compound heterozygotes.
References
Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. 2001. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 3:149-154.
Karem E, Kalman YM, Yahav Y et al. 1995. Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum Genet 96:193-197.
Kiesewetter S, Macek M, Davis C et al. 1993. A mutation in CFTR produces different phenotype depending on chromosomal background. Nat Genet 5:274-278.
Orgad S, Neumann S, Loewenthal R, Netanelov-Shapira, Gazit E. 2001. Prevalence of cystic fibrosis mutations in Israeli Jews. Genet Test 5:47-52.
Witt DR, Blumberg B, Schaefer C et al. 1992. Cystic fibrosis carrier screening in a prenatal population. Am J Hum Genet 51:A16.
Rohlfs EM, Shou Z, Sugarman EA, Heim RA, Pace RG, Knowles MR, Silverman LM, Allitto BA. 2001. The I148T CFTR mutation confers a variable phenotype and occurs on multiple haplotypes. Am J Hum Genet 69:A2600
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