ABCMdb

PMID: 20638569

Goetzinger KR, Cahill AG
An update on cystic fibrosis screening.
Clin Lab Med. 2010 Sep;30(3):533-43., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The DF508 mutation causes a protein misfold that inhibits migration of the CFTR protein from the endoplasmic reticulum to the cell membrane.1,7 Other common mutations include G542X, R553X, W1282X, N1303K, 62111 G-to-T, 1717-1 G-to-A, and R117H.8 These result in a spectrum of protein dysfunction ranging from the production of unstable RNA to CFTR cell surface instability.7 PHENOTYPIC VARIATION IN CFTR MUTATIONS Although 70% of CF patients are either homozygotes or compound heterozygotes for these 8 common mutations, there is tremendous variation in their phenotype. Login to comment 14 ABCC7 p.Arg117His ABCC7 p.Asn1303Lys Alternatively, R117H/DF508 compound heterozygotes tend to exhibit pancreatic sufficiency with varying pulmonary manifestations.9 N1303K has been associated with yet another phenotype: the early onset of pancreatic insufficiency and a wide spectrum of pulmonary disease.10 Experts have hypothesized that there are gene-environment interactions that may explain the variable pulmonary phenotype observed across the spectrum of CFTR genotypes.12,13 For example, in 2008, Collaco and colleagues12 demonstrated that any secondhand tobacco exposure had a negative long-term effect on lung function in CF patients. Login to comment 15 ABCC7 p.Arg117His These adverse effects were amplified in the presence of variants in a CF modifier gene, transforming growth factor b1 (TGFb1), thus providing support for gene-environment interactions.14 Another well-studied phenotypic variant is the R117H mutation and its association with the 5T/7T/9T polymorphism in intron 8 of the same allele. Login to comment 16 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His R117H paired with the 7T variant (in cis) and R117H paired with the 5T variant (in trans) have been observed in infertile but otherwise healthy men with congenital bilateral absence of the vas deferens (CBAVD).15,16 When this same mutation is paired with the 5T variant (in cis), signs and symptoms of classical CF are observed.17 This has led to extensive debate as to whether the R117H mutation should even be included in the prenatal screening panel Fig. 1. Login to comment 19 ABCC7 p.Arg117His Despite this fact, the R117H mutation remains a part of the standard prenatal carrier screening panel, with a reflex test for the 5T/7T/9T variant performed if positive for this mutation. Login to comment 24 ABCC7 p.Trp1282* As previously noted, the most common mutation in the Caucasian population is DF508, and the most common mutation in the Ashkenazi Jewish population is W1282X followed by DF508.18 Although Hispanics exhibit a relatively high incidence of disease, the sensitivity of carrier testing remains only 57% to 72% because detectable alleles account for only slightly more than half of the CF mutations observed in this population. Login to comment 32 ABCC7 p.Gly622Asp ABCC7 p.Gln98Arg Two additional mutations also not included in the current carrier screening panel, G622D and Q98R, were incidentally identified. Login to comment 47 ABCC7 p.Ile148Thr Based on this review, 2 mutations (1078delT and I148T) were removed from the standard screening panel, narrowing it to include only 23 mutations. Login to comment 51 ABCC7 p.Arg117His When a patient is positive for R117H, a reflex test for the 5T/7T/9T variant is sent. Login to comment 52 ABCC7 p.Arg117His ABCC7 p.Arg117His If positive for 5T, determination as to whether the polymorphism is in cis or in trans with the R117H allele is undertaken.22 As discussed previously, R117H in combination with the 5T variant in trans manifests as CBAVD, but if in cis with the 5T variant, classical CF is expressed. Login to comment 53 ABCC7 p.Arg117His ABCC7 p.Phe508Cys ABCC7 p.Ile506Val ABCC7 p.Ile507Val Given that 5% of the general population will test positive for the 5T polymorphism alone, this test is recommended only as a reflex to a positive R117H result.22,23 Non CF-causing variants, including I506V, I507V, and F508C, can mistakenly cause a false-positive result based on laboratory and testing methodologies. Login to comment 54 ABCC7 p.Phe508Cys ABCC7 p.Phe508Cys ABCC7 p.Ile506Val ABCC7 p.Ile506Val ABCC7 p.Ile507Val ABCC7 p.Ile507Val For example, in patients who screen positive for DF508 carrier status and for one of the aforementioned mutations, a false-positive test for DF508 homozygosity may be obtained, although the patient is an otherwise healthy individual.22 Although F508C has been associated with CBAVD, neither I506V nor I507V have been associated with any phenotypic manifestations of classical CF or CBAVD.24 Therefore, reflex testing for I506V, I507V, and F508C should be performed in any healthy individual who tests positive for DF508 or DI507 homozygosity, but these mutations should not be otherwise used for a priori testing. Login to comment