ABCMdb

PMID: 14711349

Richards CS, Grody WW
Prenatal screening for cystic fibrosis: past, present and future.
Expert Rev Mol Diagn. 2004 Jan;4(1):49-62., [PubMed]

Sentences

No. Mutations Sentence Comment

37 ABCC7 p.Gly542* The second most common mutation in the general Caucasian population is G542X (2.4%) [5], and there are another 4-5 above the 1% level. Login to comment 39 ABCC7 p.Trp1282* In the Ashkenazi Jewish population, the W1282X mutation is remarkably frequent (45% of carriers), improving the screening sensitivity in this ethnic group [6]. Login to comment 50 ABCC7 p.Arg117His Meanwhile, there are polymorphisms in the gene that may be harmless by themselves but influence the expression of a mutation on the same or opposite allele (e.g., R117H and 5T). Login to comment 64 ABCC7 p.Arg117His The major recommendations for population-based CF carrier screening are: • Testing should be pan-ethnic/racial and universal, though perhaps offered more aggressively to the highest risk groups (Caucasians and Ashkenazi Jews) • Testing should be in the prenatal setting, though preconception screening should be encouraged whenever possible • Whether testing sequentially or simultaneously, both members of the couple must be provided with their test results • The minimal core test panel which must be offered consists of 25 mutations and several associated polymorphisms • The intronic poly-T tract polymorphism is to be assessed only as a reflex test after an individual tests positive for the R117H mutation • Extended mutation panels beyond the core 25 are not encouraged for general population screening • Couples with positive screening results or unusual variants should be considered for referral to a genetics center for further counseling [13] While these recommendations may appear straightforward, when put into practice on a large scale (much larger and including more mutations than the pilot studies), a number of complex challenges inevitably arise. Login to comment 161 ABCC7 p.Arg117His Also considered in these models are the complex reporting situations with certain CFTR mutations, particularly R117H and 5T, and the reader is referred to these resources for a more detailed discussion. Login to comment 200 ABCC7 p.Arg117His One is the R117H mutation, which can be a CF mutation in the presence of a 5T allele on the same chromosome (cis) or a CBAVD-associated mutation when in cis with a 7T allele. Login to comment 201 ABCC7 p.Arg117His Comparison of R117H frequency in the general population versus the CF population indicates that it occurs around 20-times more frequently in the general population than predicted, which suggests that it occurs in two different forms. Login to comment 204 ABCC7 p.Arg117His Thus, the ACMG recommended that the R117H mutation be included in the screening panel (since it does cause CF) and when identified, that reflex testing for the 5T allele be performed as a routine laboratory procedure to enable more informative genetic counseling. Login to comment 209 ABCC7 p.Ile148Thr The second example of a mutation with variable expression depending on haplotype is I148T. Login to comment 212 ABCC7 p.Ile148Thr Using that standard, I148T had been reported by the CF registry at just over 0.1%. Login to comment 213 ABCC7 p.Ile148Thr Within a relatively short period following screening (<1 year), reports from large testing laboratories surfaced indicating that I148T was identified almost 100-times more frequently in the general population as compared with the CF population, a story all-too familiar at this point [46,47]. Login to comment 214 ABCC7 p.Ile148Thr Rolhfs and coworkers identified a genetic modifier, a deletion of six base pairs (3199del6), resulting in an in-frame deletion of two amino acids in the CFTR protein that traveled with I148T when it was a CF disease-causing allele [46]. Login to comment 215 ABCC7 p.Ile148Thr No CF patients were identified with I148T that did not also have 3199del6. Login to comment 216 ABCC7 p.Ile148Thr The questions then became: is 3199del6 the real CF mutation and I148T simply a polymorphism in linkage disequilibrium; does 3199del6 alone cause CF and is it ever found unlinked; or can it also be linked with other CFTR mutations? Login to comment 225 ABCC7 p.Ile148Thr A danger of expanding to more rare and less studied mutations is that their clinical significance may be questionable, as has already been experienced with I148T. Login to comment 230 ABCC7 p.Arg117His ABCC7 p.Ile148Thr The committee to review the panel of mutations has reconvened and is currently deliberating the merits of inclusion or exclusion of the R117H, 5T, I148T and 3199del6 mutations/variants. Login to comment 305 ABCC7 p.Arg117His In order to bring the laboratories up to speed on reporting for this larger and more complex panel, the ACMG recommendations included an appendix containing several model test report forms representing the major positive and negative outcomes, along with various combinations of the R117H mutation and 5T/7T polymorphisms [13]. Login to comment 308 ABCC7 p.Arg117His It is suggested that the following test result situations (among others) should prompt consideration for referral of the couple to a specialized genetics center for more lengthy and target counseling: positive-positive couples, positive-negative couples with residual anxiety, individuals with a family history of CF, individuals testing positive for R117H and the 5T/7T polymorphism, and infertile males who are found to carry a CFTR mutation or variant. Login to comment 358 ABCC7 p.Arg117His ABCC7 p.Ile148Thr The first changes are likely to be minor, perhaps involving the I148T or R117H mutations. Login to comment