ABCMdb

PMID: 15354332

Monaghan KG, Bluhm D, Phillips M, Feldman GL
Preconception and prenatal cystic fibrosis carrier screening of African Americans reveals unanticipated frequencies for specific mutations.
Genet Med. 2004 May-Jun;6(3):141-4., [PubMed]

Sentences

No. Mutations Sentence Comment

28 ABCC7 p.Ile148Thr DOI: 10.1097/01.GIM.0000127269.42279.83 May/June 2004 ⅐ Vol. 6 ⅐ No. 3 a r t i c l e Genetics IN Medicine duplex analysis (exons 4 and 13) and RFLP analysis to test for 3 additional mutations recommended by ACOG/ACMG, but not included in CF OLA v2.0 (I148T, 2184delA, and 3120ϩ1G3A, respectively). Login to comment 29 ABCC7 p.Gly622Asp During this phase of testing, G622D, Q98R, and variants of unknown clinical significance were identified by heteroduplex analysis as abnormal band shifts and were sequenced in the forward and reverse directions using the dRhodamine dye terminator sequencing kit (Applied Biosystems). Login to comment 36 ABCC7 p.Arg117His ABCC7 p.Ile148Thr Reflex testing for the 3199del6 and intron 8 polyT locus was performed for carriers of the I148T and R117H mutations, respectively. Login to comment 41 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Gly622Asp The next most common mutations detected were G622D (19%), R117H/7T (12%), which was increased compared to previous estimates of this mutant allele frequency (P Ͻ 0.001), and G551D (6%). Login to comment 44 ABCC7 p.Phe693Leu ABCC7 p.Gln98Arg Three additional sequence changes, F693L (TTG), Q98R, and P140S(C3T), were incidentally detected by heteroduplex analysis while screening for ACOG/ ACMG CF mutations not included in the test kit used during the time of screening. Login to comment 45 ABCC7 p.Gln98Arg Q98R has been reported to the CF Consortium as a disease causing mutation. Login to comment 46 ABCC7 p.Phe693Leu ABCC7 p.Pro140Ser F693L (TTG) and P140S (C3T) are variants of unknown clinical significance. Login to comment 50 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Gly622Asp ⌬F508 was the most common CF mutation identified followed by G622D, R117H/7T, and G551D. Login to comment 51 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Ile148Thr ABCC7 p.Gly622Asp ABCC7 p.Phe693Leu ABCC7 p.Gln98Arg ABCC7 p.Pro140Ser R117H has been previously reported at an increased frequency among individuals undergoing carrier screening compared to those with a diagnosis of cystic fibrosis.8 An unexpected result was the lack of 3120ϩ1G3A carriers, although 4 were expected given that this mutation accounts for Ϸ12% of the CF muta- Table 1 Summary of carrier screening results using various methods employed between December 2001 and September 2003 OLA v2.0, heteroduplex analysis (exons 4 and 13) and RFLP analysis (3120ϩ1G3A) OLA v3.0 INNO-LiPA Total screened 818 1274 97 No. of carriers identified 16 14 3 Observed carrier frequency 1/51 1/81 Mutations identified ⌬F508 (6), G622D (3), R117H/7T (3), I148T (3199del6 negative), Q98R, 1898ϩ1G3A, and G551Da ⌬F508 (14), R117H/7T, R553X, and G551D a In addition, 2 persons were positive for F693L (TTG) and 1 was positive for P140S (C3T at 550); both are variants of unknown clinical significance. Login to comment 57 ABCC7 p.Gly622Asp ABCC7 p.Phe693Leu ABCC7 p.Gln98Arg ABCC7 p.Pro140Ser Two mutations, G622D and Q98R, and two variants of unknown clinical significance, F693L (TTG) and P140S (C3T), which are not part of the recommended CF screening panel, were incidentally detected while using heteroduplex analysis to screen for ACOG/ACMG recommended mutations (Table 2). Login to comment 64 ABCC7 p.Phe693Leu ABCC7 p.Phe693Leu This is the case with F693L (TTG), which is currently classified as a CF mutation, reported on one Hispanic CF chromosome in a patient who also had the 5T allele (whether the two mutations were in-trans versus in-cis was not reported).9 However, a different base substitution in the same codon resulting in the same amino acid substitution, F693L (CTT), originally reported as a CF mutation,10 was also reported as a polymorphism.9 This mutation was later shown by functional studies to not affect the CFTR chloride channel activity or protein maturation.11 Therefore, the significance of finding F693 (TTG) in our African American population is not clear. Login to comment 65 ABCC7 p.Gln98Arg ABCC7 p.Pro140Ser P140S (C3T) has been reported in a patient with disseminated bronchiectasis, although it is not known if this mutation is associated with classic CF.9 Q98R has been reported previously as a CF mutation,12 although we are not aware of any reports of this mutation in African Americans. Login to comment 66 ABCC7 p.Gly622Asp Functional studies have demonstrated abnormal chloride channel activities for G622D.11 However, this mutation has been only reported in one patient with oligospermia and no other identifiable CF mutation on the opposite chromosome,9 so it is not known if this mutation is associated with classic CF. Login to comment 70 ABCC7 p.Gly622Asp A total of 4088 individuals (pan-ethnic), including 818 African Americans, have been screened for G622D. Login to comment 73 ABCC7 p.Ser1255* ABCC7 p.Gly480Cys ABCC7 p.Gly1249Glu ABCC7 p.Ala559Thr In addition to ⌬F508 and 3120ϩ1G3A, which are both included in the current mutation panel, other mutations outside of the ACOG/ACMG panel have been reported in African Americans (405ϩ3A3C, 444delA, ⌬F311, G480C, A559T, 2307insA, 196del54, G1249E, S1255X and D1270N6,7,13,14,15). Login to comment 80 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Ile148Thr However, laboratories, which receive a large proportion of specimens from individuals with a lower Table 2 Summary of ACOG/ACMG CF mutations identified among 2189 African Americans (4378 chromosomes) undergoing carrier screening Mutation Carriers identified Mutation frequency (%) (this study) Published mutation frequency (%)6,7 ⌬F508 20/33 61 29a -48 R117H/7T 4/33 12 1 G551D 2/33 6 1 I148T (3199del6 negative) 1/33 3 0 1898ϩ1G3A 1/33 3 1 R553X 1/33 3 0.5 3120ϩ1G3A 0 0 12-14 a The lower frequency of ⌬F508 reported by Heim et al. was most likely due to ascertainment bias. Login to comment 83 ABCC7 p.Ile148Thr As we have learned from I148T,16,17 it is of limited benefit to screen for sequence changes that do not result in a classic CF phenotype. Login to comment 85 ABCC7 p.Gly622Asp Further studies are needed on the incidence of CF mutations that are not part of the current panel, including G622D, to give an estimate of the true frequency of these alleles in African Americans and the general population in the United States. Login to comment