ABCMdb

PMID: 14500307

Curnow L, Savarirayan R, Massie J
Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H.
Arch Dis Child. 2003 Oct;88(10):886-8., [PubMed]

Sentences

No. Mutations Sentence Comment

140 ABCC7 p.Arg117His ABCC7 p.Arg117His One of the mutations in the extended mutation analysis is R117H, which is considered to be a mild CF mutation associated with a broad phenotype, ranging from no clinical disease, to CF with suppurative lung disease.3 Subjects who are compound heterozygotes for ∆F508/R117H may have raised (Cl >40 mmol/l) or normal (Cl <40 mmol/l) sweat electrolytes. Login to comment 141 ABCC7 p.Arg117His In the course of routine carrier testing following NBS, we have identified four couples in which one partner carried the ∆F508 mutation, and the other R117H. Login to comment 142 ABCC7 p.Arg117His The findings from the carrier testing raised the question of how to counsel these families regarding the carrier infant who could be a compound heterozygote (∆F508/R117H) with a normal sweat test and their risk of subsequent children being affected with CF. Login to comment 144 ABCC7 p.Arg117His The aim of this paper is to present the details of NBS and carrier testing offered to these four families and to discuss the implications for genetic counselling when both parents of ∆F508 carrier babies are found to be carriers, one with ∆F508 and the other with R117H. Login to comment 145 ABCC7 p.Arg117His We believe that this information is extremely important for centres that are already screening or considering the introduction of CF newborn screening so that appropriate genetic counselling is offered and an approach to the discovery of well infants who are compound heterozygotes with ∆F508/R117H is developed. Login to comment 149 ABCC7 p.Arg117His His father was found to be the ∆F508 carrier and his mother carried R117H. Login to comment 151 ABCC7 p.Arg117His ABCC7 p.Arg117His After genetic counselling (LC and JM) the parents elected to test the infant for R117H and he was found to be a compound heterozygote for ∆F508/R117H (9T/7T). Login to comment 152 ABCC7 p.Arg117His ABCC7 p.Arg117His The parents also elected to test their other two children aged 6 and 4 who were well, and one was also a ∆F508/R117H (9T/ 7T) compound heteroygote and the other a carrier of R117H (7T/7T). Login to comment 156 ABCC7 p.Arg117His DISCUSSION In the course of newborn screening for CF we have identified four infants who were ∆F508 heterozygotes with normal sweat electrolytes and whose parents were both identified as carriers, one with ∆F508, and one with R117H. Login to comment 158 ABCC7 p.Arg117His In each case, the infants were found to be compound heterozygotes for ∆F508/R117H. Login to comment 206 ABCC7 p.Arg117His ABCC7 p.Arg117His R117H a class IV cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, which is known to produce a CFTR protein with reduced chloride transport.4 5 The intron 8 polythymidine sequence in the gene influences the severity of the CF phenotype when R117H is found in conjunction with a severe CF mutation.6 The thymidines are found in sequences of 5(5T), 7 (7T), or 9 (9T) repeats with the fewer number of thymidines associated with less efficient mRNA splicing at the splice acceptor site with greater skipping of exon 9 in the CFTR protein. Login to comment 207 ABCC7 p.Arg117His ABCC7 p.Arg117His As a result, there is lower than normal level of full length CFTR mRNA and a decrease in mature, functional CFTR protein.7 R117H on a 5T background is acknowledged as a disease producing CFTR mutation and in combination with a severe mutation (for example, ∆F508) generally results in pancreatic sufficient CF.8 There is less known about R117H on a 7T background. Login to comment 208 ABCC7 p.Arg117His In one series, subjects were asymptomatic or had absent vas deferens only.9 A more recent series of patients known to CF clinics through clinical presentation or NBS included a small number of adults with adult onset CF disease.3 It is possible, however, that compound heterozygotes with R117H on a 7T background remain asymptomatic and are never tested. Login to comment 209 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His The range of possible phenotypes associated with the R117H mutation highlights the importance of obtaining the intron 8 polythymidine sequence prior to predicting the severity of the phenotype in an R117H compound heterozygote.10 The difficulty lies in the certainty of the information provided to parents and patients; in particular those with R117H on a 7T background. Login to comment 211 ABCC7 p.Arg117His It was explained that the infant detected by newborn screening may be a carrier of ∆F508 only or could be a compound heterozygote with ∆F508/R117H, but that it was not possible to determine which outcome was likely from the results of the sweat test alone. Login to comment 218 ABCC7 p.Arg117His With this information, the families all made the choice to test their infants for R117H. Login to comment 221 ABCC7 p.Arg117His The next decision was whether to test the healthy siblings of the carrier infant to clarify their genotypes as it was possible that they too may be compound heterozygotes with ∆F508/R117H. Login to comment 227 ABCC7 p.Arg117His ABCC7 p.Arg117His The result of the R117H testing revealed that all four infants were compound heterozygotes for ∆F508/R117H on a 7T background as were a number of their healthy siblings. Login to comment 231 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His In one series of 57 ∆F508 infants detected by NBS, five were Table 1 Details of four infants identified by newborn screening as ∆F508 carriers with both parents identified as cystic fibrosis carriers, one parent with ∆F508 and the other with R117H Newborn screening results Sweat test Parents` genotype Infant`s genotype Siblings Infant 1 IRT 99th centile Cl 28 mmol/l Mother: R117H/- ∆F508/R117H (7T/7T) F, 10 y, asymptomatic, ∆F508/R117H (7T/9T) ∆F508/- Na 21 mmol/l Father: ∆F508/- M, 12 y, asymptomatic, R117H Infant 2 IRT 99th centile Cl 18 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) M, 5 y, asymptomatic, R117H ∆F508/- Na 17 mmol/l Father: ∆F508/- Infant 3 IRT 99th centile Cl 33 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) F, 6 y, asymptomatic, ∆F508/R117H (9T/7T) ∆F508/- Na 27 mmol/l Father: ∆F508/- M, 4 y, asymptomatic, R117H (7T) Infant 4 IRT 99th centile Cl 29 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) Nil ∆F508/- Na 29 mmol/l Father: ∆F508/- Genetic counselling after carrier detection by newborn screening www.archdischild.com found to be compound heterozygotes with R117H(7T) and 10 with 5T.15 The frequency of R117H has been reported as 1% of CFTR mutations in CF patients who have been genotyped, but may be higher in the community.16 Witt et al found 0.6% of pregnant women to be R117H carriers, but this paper did not include intron 8 polythymidine sequences.17 The final issue for the four couples was to determine the frequency of follow up of healthy compound heterozygote children with ∆F508/R117H(7T). Login to comment 235 ABCC7 p.Arg117His Given the uncertain nature of the outcome of asymptomatic infants detected with R117H, it could be questioned as to the value of including it in a CFTR mutation panel. Login to comment 236 ABCC7 p.Arg117His The current technology used for the extended CFTR mutation analysis uses multiplex testing for a number of severe exon 4 mutations, and R117H is also detected. Login to comment 238 ABCC7 p.Arg117His In the future, gene sequencing may solve this problem; however, it can be argued that finding R117H on a 5T background is worthwhile as it is a disease producing mutation. Login to comment 239 ABCC7 p.Arg117His We have developed an approach to the counselling of couples who have an infant detected by newborn screening as a ∆F508 heterozygote with a normal sweat test but who are both CFTR mutation carriers, one ∆F508 and the other R117H. Login to comment 240 ABCC7 p.Arg117His It will take many years to know whether the asymptomatic compound heterozygotes with R117H on a 7T background develop features of CF to justify their early detection. Login to comment