ABCMdb

PMID: 21875427

Field PD, Martin NJ
CFTR mutation screening in an assisted reproductive clinic.
Aust N Z J Obstet Gynaecol. 2011 Dec;51(6):536-9. doi: 10.1111/j.1479-828X.2011.01348.x. Epub 2011 Aug 22., [PubMed]

Sentences

No. Mutations Sentence Comment

9 ABCC7 p.Arg117His R117H / c.350G>A was significantly increased in this infertile population and accounted for 13.8% of all mutations identified. Login to comment 17 ABCC7 p.Arg117His For example, patients with homozygous F508del/c.1521_1523delCTT usually have the most severe phenotype affecting the lungs, pancreas and intestinal tract and causing infertility in over 95% of male patients; in contrast, the affect of a R117H/c.350G>A mutation is associated with absence of the vas deferens in some male patients. Login to comment 36 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* In total, 17 different mutations were identified in this cohort of patients presenting for infertility care, with G551D/c.1652G>A, G542X/c.1624G>T, N1303K/c.3909C>G and 621+ 1G>T/c.489+1G>T being identified at a higher rate (but not significant) than the antenatal population.4 Conversely, F508delCTT/c.1521_1523delCTT, 3849+10kbC>T/c. Login to comment 37 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser549Arg Table 1 A breakdown of the CFTR mutations identified in the infertile patient population, the percentage of those mutations identified, the percentage of the infertile population screened, the percentage of the same mutations identified in the antenatal population by Massie et al. and figures published by Bobadilla et al. for the corresponding CFTR mutations in a global population study 'Legacy Mutation Name` and HGVS convention nomenclature* Number of mutations identified in infertile population Percentage of mutations identified in infertile population (%) Percentage of mutations identified in antenatal population4 (%) Percentage of mutations identified in a global population5 (%) F508delCTT / c.1521_1523delCTT 185 70.9 88.89 75.48 R117H / c.350G>A 36 13.8 0.63 G551D / c.1652G>A 12 4.6 2.78 3.82 G542X / c.1624G>T 6 2.3 0.93 1.83 N1303K / c.3909C>G 4 1.5 0.93 0.95 621+1G>T / c.489+1G>T 5 1.9 0.93 0.96 I507del / c.1519-1521delATC 2 0.8 0.53 3659delC / c.3528delC 2 0.8 R1162X / c.3484C>T 1 0.4 0.20 3120+1G>A / c.2988+1G>A 1 0.4 2184-delA / c.2052delA 1 0.4 3849+10kbC>T / c.3717-2477C>T 1 0.4 4.63 2789+5G>A / c.2657+5G>A 1 0.4 0.93 R347P / c.1040G>A 1 0.4 0.16 1717-1G>A / c.1585-1G>A 1 0.4 0.81 R553X / c.1657C>T 1 0.4 S549R / c.1647T>G 1 0.4 Total CFTR mutations identified 261 Total patients screened 5600 Incidence of CF carriers at QFG 1 in 21.5 (4.66%) CF, cystic fibrosis; CFTR, CF transmembrane receptor. Login to comment 40 ABCC7 p.Arg117His R117H/c.350G>A, the CFTR mutation previously linked to infertility in male patients, was identified at 13.8% of all mutations identified in our population of ART patients (12.2% in women and 18.5% in men) compared with the global population of 0.6%.5,6 Twelve carrier couples were identified during this study with nine of those couples progressing to at least one cycle of PGD for CF. Login to comment 42 ABCC7 p.Arg117His Discussion In a worldwide analysis of CFTR mutation rates, Bobadilla et al. published mutation rates by continent and country, giving a global snapshot of CFTR mutations in many populations5 (see Table 1), which is mirrored by results published by the WHO.6 Screening of 5600 patients presenting for infertility treatment identified a CFTR mutation carrier rate that is elevated when compared to that identified in a comparable Australian antenatal population screen4 as well as global populations.5,6 Our results are biased with regard to the sex of mutation carriers as mostly female ART patients (84%) were screened; however, this is comparable with the percentage of female patients included in the antenatal population from the published data set of Massie et al.4 Our data suggest a link between female infertility and some of the less common CFTR mutations eg R117H/c.350G>A. Login to comment 43 ABCC7 p.Arg117His ABCC7 p.Arg117His Male carriers of the R117H/c.350G>A mutation have been shown to have an increased association with congenital absence of vas deferens (CAVD) with 22%7 and 24%8 carrier rates reported in men affected with CAVD, but the link between R117H/c.350G>A and infertility has never been shown with female patients. Login to comment 44 ABCC7 p.Arg117His Radpour et al. investigated the link between CFTR mutations and congenital absence of the uterus and vagina but only identified links between CAVD and CFTR mutations in male carrier patients.9 Female patients affected with CF are known to have reduced fertility, not only owing to tenacious impermeable cervical mucus, but affected female patients also have some ovarian dysfunction as well as reduced nutrition.10 We believe that the increased incidence of R117H/c.350G>A mutation in this study being at 13.8%, compared to a background population level of under 0.65%, shows some association with both female and male infertility. Login to comment 47 ABCC7 p.Arg117His ABCC7 p.Arg117His Only one other major study reported a similar level of R117H/c.350G>A at a rate of 16% of all mutations identified (carrier rate of one in 27 in a 12 mutation panel) in 5161 pregnant patients from California.13 A larger study of 57 999 patients screened for CFTR mutations over a ten-year period has shown that medically assisted reproduction couples had a carrier rate of one in 22 compared to the antenatal population incidence of one in 32 but found a much lower incidence of R117H/c.350G>A in their ART patients.14 Studies have shown that when a carrier screening program for CFTR mutations is implemented, the live birth rate of babies affected by CF has been reduced.15-18 A screening study in New South Wales, Australia, screened 1000 patients and found that those patients at highest risk of having a CF-affected child altered their reproductive plans to avoid having an affected baby.19 The study published after screening 3000 female antenatal patients in Victoria, Australia, identified nine carrier couples, six of those couples chose to terminate their pregnancy because of a prenatal result showing their baby was affected.4 From the patients screened at this clinic, we were able to identify 12 carrier couples, nine of which went on to have at least one cycle of PGD for CFTR mutations. 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