ABCMdb

PMID: 15371906

Kornreich R, Ekstein J, Edelmann L, Desnick RJ
Premarital and prenatal screening for cystic fibrosis: experience in the Ashkenazi Jewish population.
Genet Med. 2004 Sep-Oct;6(5):415-20., [PubMed]

Sentences

No. Mutations Sentence Comment

14 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Although the demand for screening was great, widespread population screening was not actually recommended by the American College of Obstetrics and Gynecology (ACOG) and American College of Medical Genetics (ACMG) until 2001.5 Based on a frequency of at least 0.1% of mutant alleles in a large CF patient database, a panel of 25 mutations was recommended even though the sensitivity was still below 90% in most ethnic groups.6 The results of screening with this mutation panel were reviewed in 20027 and most recently, in this issue.8 The Ashkenazi Jewish (AJ) population represents a unique group for genetic screening as common mutations occur in prevalent recessive diseases due to founder effect and/or selection.9,10 With regard to CF, five CFTR mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) account for 97% of the mutant alleles in AJ CF patients.11 This population has a very high acceptance rate for genetic screening and has had a positive experience with carrier screening, beginning with Tay-Sachs disease in 1970.12,13 In this study, we report our experiences with CF carrier screening in the AJ population using two different approaches: premarital (Dor Yeshorim, DY) and prenatal screening (Mount Sinai School of Medicine, MSSM). Login to comment 19 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp1152His DOI: 10.1097/01.GIM.0000139510.00644.F7 September/October 2004 ⅐ Vol. 6 ⅐ No. 5 a r t i c l e Genetics IN Medicine Jewish community, began premarital screening in 1983 for Tay-Sachs.14 CF was added to their premarital testing panel in 1993.15 The Genetic Testing Laboratory at MSSM has been conducting prenatal CF carrier screening since 1992 and has performed over 60,000 CF tests.16 Both programs initially screened for five, reported common AJ mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K).11 In 2000, DY observed the presence of the D1152H CF mutation in the AJ population and, therefore, added this mutation along with 1717-1 GϾA to its routine AJ screening panel. Login to comment 22 ABCC7 p.Asp1152His In 2001, MSSM began screening the AJ population for the remaining 25 ACMG recommended panethnic mutations along with D1152H. Login to comment 29 ABCC7 p.Asp1152His The second subset was tested for the 25 ACMG recommended CFTR panethnic mutation panel and D1152H. Login to comment 32 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* For the DY cohort, all individuals were initially tested for five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K). Login to comment 33 ABCC7 p.Asp1152His Subsequently, the DY panel was increased to seven with the addition of D1152H and 1717-1GϾA. Login to comment 36 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* At MSSM, for the period January 1997 through December 2000 for which data and ethnic information are available, five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) were analyzed by PCR amplification and restriction enzyme analyses. Login to comment 37 ABCC7 p.Asp1152His From January 2001, the panel was expanded to 26 mutations (the ACMG recommended panethnic panel plus D1152H). Login to comment 41 ABCC7 p.Trp1282* W1282X was most frequently detected by both programs with a carrier frequency of Ϸ1 in 50 (or Ϸ0.020). Login to comment 43 ABCC7 p.Asp1152His Of note, the third most common mutation, D1152H, was detected in about 1 in 190 of the 44,530 screenees tested (0.0053). Login to comment 45 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The G542X, 3849ϩ10 kb CϾT, and N1303K were tested in over 117,000 screenees and occurred at similar frequencies in both programs, with overall detection rates of 1 in 413 (0.0024), 1 in 490 (0.0020), and 1 in 633 (0.0016), respectively. Login to comment 47 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* For the five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) for which over 117,000 AJ screenees were tested, a total of 4,498 carriers were identified (1 in 26 or 0.038). Login to comment 48 ABCC7 p.Asp1152His For D1152H and 1717-1GϾA, 235 and 9 carriers were detected among 44,530 and 60,191 screenees, respectively. Login to comment 54 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ile148Thr Among the over 2,300 AJ screenees tested, one screenee was identified who carried R117H, one carried G551D and two carried I148T. Login to comment 55 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr The two I148T carriers were tested for the 3199del6 mutation by direct sequencing and were found to be negative for this putative-disease causing mutation.18-20 In the DY program, over 7,000 100% AJ individuals were screened for up to 87 mutations and only one screenee was found to be an I148T carrier and another was an 1898ϩ1GϾA carrier. Login to comment 56 ABCC7 p.Trp1282* ABCC7 p.Asp1152His Five individuals from four families in the DY program were found to be compound heterozygotes for D1152H and W1282X (2 families), ⌬F508 (1), or 3849ϩ10kb CϾT (1). Login to comment 57 ABCC7 p.Trp1282* ABCC7 p.Asp1152His Two individuals with the D1152H/W1282X genotype had digestive problems and growth retardation without significant pulmonary problems. Login to comment 61 ABCC7 p.Asp1152His If D1152H was not included, the carrier rate was 1 in 29.8. Login to comment 62 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Ile148Thr The additional mutations that were detected were R117H (n ϭ 7), I148T (6), A455E (2), R334W (2), G551D (1), and R553X (1). Login to comment 68 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp1152His ABCC7 p.Asp1152His Of the remaining 31 prenatal diagnoses, 24 fetuses were heterozygotes and Table 1 Carrier frequencies of seven routinely tested AJ CF mutations CF mutation No. individuals tested Frequency Combined frequency Previous studies DY MSSM DY MSSM Ref 3 n ϭ 6076 Ref 15 n ϭ 6850 W1282X 110889 6247 1 in 49.7 (0.0201) 1 in 48.8 (0.0205) 1 in 49.6 (0.0202) 1 in 48.2 (0.0207) 1 in 48.2 (0.0207) ⌬F508 110898 6247 1 in 81.7 (0.0122) 1 in 86.8 (0.0115) 1 in 82.0 (0.0122) 1 in 79.7 (0.0126) 1 in 77.9 (0.0128) D1152H 42208 2322 1 in 189.2 (0.00528) 1 in 193.5 (0.00517) 1 in 189.5 (0.00528) 1 in 113.5a (0.00881) NDb G542X 110893 6247 1 in 410.7 (0.00243) 1 in 446.2 (0.00224) 1 in 412.5 (0.00242) 1 in 338.3 (0.00296) 1 in 506.3 (0.00197) 3849ϩ10kb CϾT 110888 6247 1 in 490.7 (0.00204) 1 in 480.5 (0.00208) 1 in 490.1 (0.00204) 1 in 402.9 (0.00248) 1 in 607.6 (0.00165) N1303K 110894 6247 1 in 637.2 (0.00157) 1 in 567.9 (0.00176) 1 in 633.2 (0.00158) 1 in 913.3 (0.00109) 1 in 552.4 (0.00181) 1717-1 GϾA 57869 2322 1 in 7233.6 (0.000138) 1 in 2322 (0.000431) 1 in 6687.9 (0.000150) NDb NDb Five mutations (Without D1152H and 1717-1 GϾA) 1 in 26.1 (0.0384) 1 in 26.2 (0.0381) 1 in 26.1 (0.0384) 1 in 25.1 (0.0398) 1 in 25.7 (0.0389) Seven mutations 1 in 22.8 (0.0438) 1 in 22.9 (0.0437) 1 in 22.8 (0.0438) a n ϭ 1305. b Not determined. Login to comment 69 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp1152His Table 2 Distribution of CF mutations in DY and MSSM carriers for five and seven common AJ mutations CF mutation % of AJ carriers (5 mutations) % of AJ carriers (7 mutations) DY MSSM Combined DY MSSM Combined W1282X 52.3 53.8 53.1 45.9 46.9 46.4 ⌬F508 31.9 30.2 31.0 27.9 26.3 27.1 G542X 6.3 5.9 6.1 5.5 5.1 5.3 3849ϩ10kb CϾT 5.3 5.5 5.4 4.7 4.8 4.8 N1303K 4.1 4.6 4.4 3.6 4.0 3.8 D1152H - - - 12.1 11.8 12.0 1717-1GϾA - - - 0.3 1.0 0.6 seven did not carry either parental mutation. Login to comment 83 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Previous studies of AJ patients with CF indicated that screening for five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) would detect 97% of alleles causing CF in the AJ population.11 Based on the data presented in this study, the largest dataset on AJ carrier screening reported to date, the CF carrier frequency in the 100% AJ population is about 1 in 26 for these five mutations (Table 1). Login to comment 86 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Asp1152His For example, W1282X was the most prevalent mutation among Ashkenazi Jews, present in 46.4% of AJ carriers, whereas it was present in only 1.5% of non-Hispanic Caucasian CF patients.8 ⌬F508, the most common mutation in non-Hispanic Caucasian CF pa- Table 3 Frequency of CFTR mutations among screenees reporting 100% AJ or Ͻ 100% AJ descent who requested carrier testing for CF and at least one other AJ recessive disease CF mutation % of mutations in carriers reporting 100% AJ descent (n ϭ 45,530-117,145) % of mutations among carriers reporting Ͻ100% AJ descent (n ϭ 7,393) % of Non-Hispanic Caucasian CF patient chromosomes8 (n ϭ 37,263) W1282X 46.4 (n ϭ 117,136) 32.3 1.5 ⌬F508 27.1 (n ϭ 117,145) 35.7 71.5 D1152H 12.0 (n ϭ 44,530) 8.7 0.03 G542X 5.3 (n ϭ 117,140) 6.1 2.3 3849ϩ10kb CϾT 4.8 (n ϭ 117,135) 4.9 0.7 N1303K 3.8 (n ϭ 117,141) 3.0 1.3 1717-1GϾA 0.6 (n ϭ 60,191) 1.9 0.7 R117H a 2.7 0.8 I148T a 2.3 0.05 R334W - 0.76 0.16 A455E - 0.76 0.19 G551D a 0.38 2.5 R553X - 0.38 1.0 a These mutations were detected when screening Ϸ2,300 100% AJ individuals with the ACMG recommended panel. Login to comment 89 ABCC7 p.Asp1152His ABCC7 p.Asp1152His The D1152H and 1717-1GϾA mutations were added to the DY screening panel in 2000 and MSSM added the remaining mutations in the ACMG panel of 25 panethnic mutations along with D1152H in 2001. Login to comment 90 ABCC7 p.Asp1152His D1152H has a carrier frequency of 1 in 190 (or 0.0053) in the AJ population, where it represents 12% of the CF carrier alleles. Login to comment 91 ABCC7 p.Asp1152His Functional studies indicated that D1152H, located in the intracytoplasmic loop connecting transmembrane domain 12 and nucleotide binding domain 2, did not alter the maturation of the CFTR protein, but interfered with proper gating of the chloride channel.21 Mutation 1717-1GϾA was included in the ACMG recommended CF panethnic mutation panel (0.7% of CF chromosomes)8 so it was routinely tested as part of the MSSM program as well as most of the academic and commercial laboratories who now test the DY screenees. Login to comment 93 ABCC7 p.Asp1152His Of note, this mutation was not detected when over 7000 Israeli Jews were screened.3 When D1152H and 1717-1 GϾA were included, the overall AJ carrier frequency increased to 1 in 23. Login to comment 94 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ile148Thr When MSSM and DY testing laboratories introduced expanded screening panels, several other CF mutations were found among AJ screenees; these were R117H, G551D, I148T, and 1898ϩ1GϾA. Login to comment 95 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Of interest, R117H and G551D represented 0.8 and 2.5% of alleles in the non-Hispanic Caucasian CF patients, respectively,8 but were rare in the AJ population (each seen only once in over 2,300 screenees). Login to comment 96 ABCC7 p.Ile148Thr In addition, three screenees were found to carry I148T. Login to comment 97 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Ile148Thr ABCC7 p.Asp1152His ABCC7 p.Asp1152His However, the two individuals identified at MSSM were found to be negative for the 3199del6 mutation that presumably is the disease-causing mutation in cis with the I148T variant.18-20 Of the five individuals identified by DY who were compound heterozygotes for D1152H and W1282X, ⌬F508 or 3849ϩ10kb CϾT, anecdotal information from the two individuals from one family with the D1152H/W1282X genotype indicated a mild form of CF. Login to comment 99 ABCC7 p.Gly542* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His However, previous reports indicate that the D1152H mutation together with a classic CF mutation results in variant CF phenotypes, including an adult (D1152H/ ⌬F508) with mild pulmonary disease.22 The D1152H/⌬F508 genotype also has been reported in four adults with mild pulmonary symptoms, two with Pseudomonas colonization, and another with pancreatic insufficiency.23,24 This mutation has also been observed in males with CBAVD.25,26 However, this mutation was present along with G542X in a fetus with hyperechogenic bowel loops and meconium ileus, suggesting a more severe course would occur in this case.27 In contrast to the limited number of CFTR mutations that were detected in screenees who reported themselves to be 100% AJ, the distribution of CFTR mutations in the over 7,000 MSSM screenees who were of Ͻ 100% AJ descent differed significantly. Login to comment 101 ABCC7 p.Trp1282* Of interest, W1282X, which was the most prevalent mutation seen in the 100% AJ cohort (46.4% of CFTR mutations), was observed in 32.3% of the population with Ͻ 100% AJ descent. Login to comment 104 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp1152His Based on the results of these studies, it is recommended that premarital/prenatal carrier screening for CF be performed by testing the five common AJ CFTR mutations (W1282X, DF508, G542X, 3849ϩ10kb CϾT, N1303K), along with D1152H, for individuals who report that they are 100% AJ. Login to comment 105 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Genetic counseling for at risk couples carrying D1152H and a classic CF mutation should include the latest clinical information about CF patients with the D1152H lesion for informed decision-making. Login to comment 107 ABCC7 p.Ile148Thr Approximately half of the MSSM 100% AJ screenees were also tested for the ACMG 25 panethnic mutation panel and only two had another mutation, excluding I148T. Login to comment 109 ABCC7 p.Asp1152His Therefore, in the later situations, it is recommended that the revised ACMG screening panel of 23 mutations and D1152H (with proper counseling) be used for CF carrier screening. Login to comment