ABCMdb

PMID: 15789152

Langfelder-Schwind E, Kloza E, Sugarman E, Pettersen B, Brown T, Jensen K, Marcus S, Redman J
Cystic fibrosis prenatal screening in genetic counseling practice: recommendations of the National Society of Genetic Counselors.
J Genet Couns. 2005 Feb;14(1):1-15., [PubMed]

Sentences

No. Mutations Sentence Comment

133 ABCC7 p.Arg117His ABCC7 p.Ile148Thr In addition, mutations such as R117H and I148T have been found at unexpectedly high frequencies in healthy populations, suggesting that they are not completely penetrant (Rohlfs et al., 2002; Strom et al., 2002; Witt et al., 1996). Login to comment 134 ABCC7 p.Arg117His Further evidence for a variable phenotypic effect of these and other mutations is found by the observation of the same genotype ( F508/R117H) in individuals with and without disease. Login to comment 141 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* and Class III mutations such as W1282X, F508, and G551D result in little or no functional CFTR channel activity, and are usually associated with the classic CF phenotype of pulmonary disease, elevated sweat chlorides, pancreatic insufficiency, and male infertility. Login to comment 155 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Mutations described as "severe,"forexample, F508, I507,G542X,G551D, W1282X, N1303K, R553X, 621 + 1G>T, and 1717-1G>A, are usually categorized as Class I, II, or III, and the expected pancreatic insufficient phenotype occurs when one of these mutations is inherited in trans with a second mutation, of Class I, II, or III. Login to comment 156 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Mutations described as "mild", for example, R117H, R334W, R347P, and A455E (Kristidis et al., 1992; The CF genotype-phenotype consortium, 1993), are more likely to be associated with pancreatic sufficiency regardless of the class of the second mutation. Login to comment 168 ABCC7 p.Trp1282* COMPLEX ALLELES While phenotypic expression of autosomal recessive disorders typically results from the presence of a causative mutation in each allele of the pair, for example, F508 mutation on one chromosome and W1282X on the other, CF screening has unmasked a diagnostic and counseling challenge in the form of complex alleles. Login to comment 169 ABCC7 p.Arg117His ABCC7 p.Ile148Thr Complex CFTR genotypes-where more than one CFTR mutation or variant is present in the same copy of the gene (in cis) and the presence or absence of that variant affects phenotype- characterize two common CFTR mutations, I148T and R117H. Login to comment 170 ABCC7 p.Ile148Thr With an allele frequency of 0.1% among affected CF patients, I148T is included in the ACMG/ACOG recommended panel (Grody et al., 2001). Login to comment 171 ABCC7 p.Ile148Thr After testing for I148T in the general population, it has become apparent that its frequency among apparently healthy individuals is 60-100 times that expected based on the CF affected population (Buller et al., 2004). Login to comment 172 ABCC7 p.Ile148Thr In addition, several asymptomatic individuals (including fertile males) were identified as compound heterozygotes for I148T and other CF mutations (Rohlfs et al., 2002; Strom et al., 2002). Login to comment 173 ABCC7 p.Ile148Thr These observations led to the identification of the 3199del6 allele whose presence in cis with the I148T allele influences phenotype (Rohlfs et al., 2002). Login to comment 174 ABCC7 p.Ile148Thr Among 8 apparently healthy adults who were compound heterozygotes or homozygotes for I148T, all were negative for 3199del6. Login to comment 175 ABCC7 p.Ile148Thr In contrast, 7 of 8 individuals with a suspected or confirmed clinical diagnosis of CF had the 3199del6 allele in cis with I148T and a second CF mutation on the other chromosome. Login to comment 176 ABCC7 p.Ile148Thr I148T in the absence of 3199del6 appears to be a polymorphism, given its presence in apparently healthy adults who are compound heterozygotes. Login to comment 177 ABCC7 p.Ile148Thr Further studies would be required to determine whether I148T alone with a CFTR mutation on the other chromosome is associated with single-organ or late onset expression of disease. Login to comment 178 ABCC7 p.Ile148Thr Counseling for I148T positive individuals is therefore best done with knowledge of 3199del6 status. Login to comment 179 ABCC7 p.Ile148Thr The ACMG Cystic Fibrosis Working Group has recommended the removal of I148T from the ACMG panel because 3199del6 is the pathogenic finding (Watson et al., 2004). Login to comment 181 ABCC7 p.Arg117His The R117H mutation is also a complex allele, occurring on different intron 8 polythymidine ("polyT") backgrounds: 5T or 7T (Kiesewetter et al., 1993). Login to comment 182 ABCC7 p.Ile148Thr As with I148T, the background contributes to the phenotypic expression. Login to comment 184 ABCC7 p.Arg117His The R117H mutation has been reported to occur on the same chromosome as the 5T or 7T intron 8 variants. Login to comment 185 ABCC7 p.Arg117His Individuals with a disease-causing CF mutation on one chromosome (such as F508) and an R117H mutation on the other have been reported with a variety of clinical presentations: no symptoms (Massie et al., 2001), congenital absence of the vas deferens in males (Dork et al., 1997), chronic pancreatitis (Noone et al., 2001), and nonclassic and pancreatic sufficient CF (Kiesewetter et al., 1993; Massie et al., 2001). Login to comment 187 ABCC7 p.Arg117His ABCC7 p.Arg117His However, individuals with F508 (or another CF mutation) on one chromosome, and R117H/5T in cis on the other chromosome, would be expected to have cystic fibrosis (likely pancreatic sufficient), whereas an individual with a CF mutation on one chromosome and R117H in cis with 7T or 9T on the opposite chromosome (Massie et al., 2001; Chu et al., 1993) is more likely to be asymptomatic or have milder symptoms, e.g. CBAVD in males. Login to comment 189 ABCC7 p.Arg117His Current carrier testing recommendations therefore include performing polyT variant analysis reflexively for individuals identified as R117H positive. Login to comment 190 ABCC7 p.Arg117His POLY T The poly T tract in intron 8 poses counseling challenges, regardless of the presence of R117H. Login to comment 204 ABCC7 p.Arg117His Testing for the 5T allele may help to identify the etiology of CBAVD or nonclassic CF symptoms (Kere et al., 1997; Richards et al., 2002), in addition to its use in reflex testing for R117H. Login to comment