ABCMdb

PMID: 15371904

Rohlfs EM, Weinblatt VJ, Treat KJ, Sugarman EA
Analysis of 3208 cystic fibrosis prenatal diagnoses: impact of carrier screening guidelines on distribution of indications for CFTR mutation and IVS-8 poly(T) analyses.
Genet Med. 2004 Sep-Oct;6(5):400-4., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Arg117His However, more than 40% of these cases could be attributed to parental R117H mutations. Login to comment 12 ABCC7 p.Arg117His They also recommend that laboratories offering CF screening include a minimum of 25 specific mutations in their panel, with additional mutations included if warranted by the local demographics.10,11 Included in the ACMG/ACOG 25 mutation panel is R117H, a mutation known to have variable phenotypic expression. Login to comment 13 ABCC7 p.Arg117His When R117H is identified during carrier screening, the guidelines recommend additional testing to determine the length of the intron 8 polythymidine tract (poly(T)). Login to comment 14 ABCC7 p.Arg117His When R117H is found in cis with 5 thymidines (5T), and trans to a severe CF mutation, individuals may have moderate (i.e., pancreatic sufficient) CF. Login to comment 15 ABCC7 p.Arg117His ABCC7 p.Arg117His When R117H is identified in cis with 7 thymidines (7T) and in trans to a CF mutation individuals may be asymptomatic, have congenital absence of the vas deferens (CAVD), or later onset lung disease (i.e., a milder phenotype).12,13 In addition to being identified on the same chromosome as R117H, the 5T allele occurs alone in approximately 10% of the general population.12 When the 5T allele is included in CF From the 1 Genzyme Corporation, Genzyme Genetics, Molecular Diagnostic Laboratory, Westborough, Massachusetts; 2 Genzyme Genetics, Philadelphia, Pennsylvania. Login to comment 62 ABCC7 p.Arg117His A significant number of these tests could be attributed to parental R117H mutations. Login to comment 63 ABCC7 p.Arg117His More than 50% of those cases with a family history of CF or a CF carrier that were tested for poly(T), were at risk for inheriting an R117H mutation. Login to comment 64 ABCC7 p.Arg117His The two prenatal screening cases that were also tested for poly(T), were done so after identification of R117H in the fetus. Login to comment 75 ABCC7 p.Arg117His with R117H carrier parent (%) Unrelated to 5T status 3116 (97.1) 47 (1.6) 20 (42.6) Abnormal fetal ultrasound 1232 (38.4) 10 (0.8) 2 (20.0) Family history of CF or CF carrier 1176 (36.7) 35 (3.0) 18 (51.4) Prenatal screening 708 (22.0) 2 (0.3) 0 Related to 5T status 92 (2.9) 92 (100) 7 (7.6) Fetus at risk for 5T and CF mutation in trans 48 (1.5) 48 (100) 7 (14.6) One or both parents positive for only 5T 44 (1.4) 44 (100) 0 All indications 3208 139 (4.3) 27 (19.4) DISCUSSION Our purpose was to determine the frequency of specific indications for prenatal CFTR and poly(T) testing and to determine if the ACMG/ACOG CF screening statement influenced the frequency of these requests. Login to comment 93 ABCC7 p.Arg117His As a result, the ACMG/ACOG guidelines specifically state that screening for 5T alleles should only be performed when the R117H mutation is identified. Login to comment 98 ABCC7 p.Arg117His ABCC7 p.Arg117His When those cases related to an R117H mutation are excluded (i.e., parental or fetal R117H), the percentage drops further to 0.8%. Login to comment 99 ABCC7 p.Arg117His Providing poly(T) information in the context of an R117H mutation is recommended by the ACMG/ACOG carrier screening guidelines and is necessary and appropriate for the genetic counseling process. Login to comment 104 ABCC7 p.Arg117His In summary, we find that the frequency of prenatal referral indications shifted after publication of the CF carrier screening guidelines and that poly(T) testing is not routinely ordered on prenatal specimens unless one of the parents has been previously identified with a 5T allele or carried an R117H mutation. Login to comment