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Immunoreactive Trypsin/DNA Newborn Screening for Cystic Fibrosis: Should the R117H Variant Be Included in CFTR Mutation Panels?

^a Institut National de la Santé et de la Recherche Médicale Inserm U613 Génétique Moléculaire et Génétique Épidémiologique, Brest, France
^b Laboratoire de Génétique Moléculaire, CHU Morvan, Brest, France
^c Centre de Ressources et de Compétences sur la Mucoviscidose, Rennes, France
^d Centre de Ressources et de Compétences sur la Mucoviscidose, Roscoff, France
^e Centre de Ressources et de Compétences sur la Mucoviscidose, Vannes, France

	ABSTRACT

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BACKGROUND. Cystic fibrosis newborn screening is now implemented universally in France, as well as in many states in the United States and in various areas of Europe and Australia. Because the screening protocol usually includes the analysis of the most common CFTR mutations, it is of the utmost importance that only mutations that result in classical cystic fibrosis are included in this test. The panels of mutations used in most cystic fibrosis newborn screening programs enable the detection of a relatively frequent CFTR variant (R117H) whose implication in cystic fibrosis remains unclear. Physicians, therefore, have difficulty managing detected compound heterozygotes with this variant, which raises the issue of the appropriateness of extended testing in families and of the legitimate use of prenatal diagnosis.

OBJECTIVE. The aim of this study was to describe the clinical outcome of the children found to be compound heterozygous for R117H by screening in Brittany (western France), where cystic fibrosis newborn screening was set up in 1989, and to assess whether this CFTR variant should be included in the newborn screening mutation panels.

METHODS. Data on clinical status were obtained by the referring pediatricians.

RESULTS. Since our screening protocol has enabled detection of R117H (ie, in 1995), 360466 newborns have been screened for cystic fibrosis in Brittany, of whom 124 had elevated immunoreactive trypsin and 2 mutations in the CFTR gene. Nine of these children (7.3%) were compound heterozygous for R117H, which in all cases was linked to the 7T_11TG haplotype [IVS8-nT variant/m(TG) repeat]. Their genotypes were F508del/R117H (n = 7), I507del/R117H (n = 1), or G551D/R117H (n = 1). At the time of this writing, the mean age of these 9 children was 7.0 years (the oldest being >10 years of age), and none of them had yet developed any signs of cystic fibrosis; they have been pancreatic sufficient and have had good nutritional status and pulmonary function. Moreover, we observed that, in Brittany, all the patients carrying the R117H variant have been identified exclusively through cystic fibrosis newborn screening.

CONCLUSIONS. In view of the high frequency of R117H-7T identified by cystic fibrosis newborn screening, the uncertain outcome of the asymptomatic children, and physicians' difficulty in managing these situations, we propose the withdrawal of the R117H variant from the panels of CFTR mutations used in cystic fibrosis newborn screening, given the expanding implementation of cystic fibrosis newborn screening.

Key Words: cystic fibrosis • newborn screening • R117H • genetic counseling • Brittany

Abbreviations: CF—cystic fibrosis • CFNS—cystic fibrosis newborn screening • IRT—immunoreactive trypsin • CFTR—cystic fibrosis transmembrane conductance regulator • nT—n thymidines • FEV₁—forced expiratory volume in 1 second • FVC—forced vital capacity

Brittany was among the first areas in the world to implement a pilot program of cystic fibrosis (CF) newborn screening (CFNS).¹ It was set up 17 years ago (in 1989) in this region of western France, where the incidence of CF is particularly high.² By 2002, CFNS has progressively been extended to the whole of France, which became the second country to implement nationwide CFNS, after New Zealand.^3,4 To date, screening has been implemented in many states in the United States, as well as in various areas of Europe and Australia.

Currently, the CFNS protocol usually combines the assay of a pancreatic enzyme (immunoreactive trypsin [IRT]) with the analysis, in case of high IRT, of the most common mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. More than 1400 mutations have been found in this gene. In France, the molecular part of the screening protocol relies on the use of a kit of 30 mutations (Elucigene CF30; Tepnel Diagnostics Ltd, Abingdon, Oxfordshire, United Kingdom), and the first results of this program have revealed the high frequency of one variant (R117H), which now seems to be the most frequent after the main F508del mutation. The first 2-year experience of the French CFNS program shows that this variant has been found in 7.2% of the newborns screened positive with 2 CFTR mutated alleles (18 of 249 newborns, including 16 compound heterozygotes for R117H and 2 homozygotes for this variant).⁴ Similar findings have been reported elsewhere. For example, CFNS in Massachusetts found that 8.0% of the CF-affected newborns carried R117H as 1 of their 2 abnormal CFTR alleles (9 of 112).⁵ The situation is quite different, however, in the CFNS program of Wisconsin, where this frequency reaches 26.7% (8 of 30 newborns detected from March 2002 to June 2003).⁶ Because these 8 infants had normal or borderline sweat-test values, they were not included in the calculation of CF incidence in the state.

The R117H variant, which is located in exon 4 of the CFTR gene, belongs to the class IV mutations, which are known to produce a CFTR protein that affect ion conductance.⁷ The implication of this variant in CF remains ambiguous. The phenotype of subjects who are compound heterozygous for a severe CFTR mutation and R117H can range from a classical form of CF to congenital bilateral absence of vas deferens or even to no clinical disease, especially in women. This large phenotypic heterogeneity may be explained in part by the efficiency of exon-9 splicing, which is influenced by a polythymidine sequence of intron 8 of the CFTR gene (IVS8-nT), which can include a succession of 5 (5T), 7 (7T), or 9 thymidines (9T).⁸ The length of this tract influences the efficiency of mRNA splicing, with a decrease in mature functional CFTR protein observed for the shorter alleles.^9–11 This is why a given F508del/R117H genotype can be associated with a mild form of CF characterized by pancreatic sufficiency and moderate lung disease (when it is found in cis with the 5T allele), with male infertility only, or even with absence of any clinical signs (when it is found in cis with the 7T allele).^8,12–15 The efficiency of mRNA splicing is also modulated by the length of a polymorphic TG locus [m(TG)], which is located just upstream of the polythymidine sequence. The number of TG repeats ranges from 9 to 13, and a decrease in mature functional CFTR protein is observed for the longer alleles.¹⁶

According to the North American Cystic Fibrosis Foundation Consensus Panel,¹⁷ only the R117H-5T haplotype is considered to be a disease-causing mutation, but this is still a matter of debate in the clinical community. The other form (R117H-7T) is detected most frequently in the screening protocols (frequency ranges from 70% to 100% in white populations).^6,18–20 Whereas R117H-5T acts as a deleterious mutation, the situation is less clear for R117H-7T. Most subjects who are compound heterozygous for R117H on a 7T background have normal or borderline sweat test results, and it is probable that the majority of them will not progress toward CF symptomatology. However, because delayed manifestations of CF lung disease have been observed in some older subjects,^18,21,22 we have no real data indicating how many patients will remain asymptomatic.

Because the outcome of children found to be compound heterozygous for R117H-7T remains difficult to predict at this time, it is hard to offer satisfactory genetic counseling to the families concerned.²³ There are questions of how to counsel the parents: Which information should be given to the parents of a compound heterozygous child with normal sweat test results? What should be the frequency of the follow-up of such an asymptomatic child? Should there be extended testing in families, that is, should a test be offered to siblings who have a high risk of having the same genotype? Should this information be used for prenatal diagnosis? This matter is all the more significant in the areas in which the use of prenatal diagnosis is very common and the option of a therapeutic abortion is frequently chosen (as is the case in our area).

The aim of this article was to review the data of the 16 years of experience of CFNS in Brittany in order to present the clinical outcome of the children screened positive with an R117H-7T and a second severe CFTR mutation. To date, our screening protocol has identified 9 children as compound heterozygous for R117H, which in all cases was linked to the IVS8-7T variant. These data lead us to reconsider our position and to wonder whether R117H should be included in mutation panels.

	METHODS

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Newborn Screening for CF in Brittany
A pilot program of newborn screening for CF was implemented in Brittany in 1989.¹ Since then, 2 protocols have successively been used: first an IRT/IRT protocol and then, from 1992, an IRT/DNA analysis protocol. Only samples with an IRT concentration that was higher than the decisional cutoff were studied by a second tier of DNA testing. This molecular analysis initially relied on the direct amplification of 3 exons of the CFTR gene (exons 7, 10, and 11) and was followed by an extended analysis when only 1 mutation was identified by this protocol and when the sweat tests performed by the referral method at 3 months were positive. This extended molecular analysis had enabled the detection of the R117H variant since 1995. Since the implementation of the CFNS program in the whole of France in 2002, the initial analysis of 3 exons of the CFTR gene has been replaced by the use of a kit of 30 mutations (Elucigene CF30), which directly enables identification of the R117H variant. The decisional cutoff for the IRT assay has changed over time: it was 600 µg/L from 1989 to November 1992, 700 µg/L from December 1992 to 1997, and 1000 µg/L from 1998 to 2001. The technics have changed with the implementation of the nationwide screening program by 2002; the cutoff was 60 ng/mL for the first 2 years and has been 65 ng/mL since 2004.

Study Population
Our study population was the cohort of children screened for CF in Brittany since 1995, when the CFNS protocol first enabled detection of the R117H variant. From January 1, 1995, to December 31, 2004, 360466 newborns were screened for CF in Brittany. Among them, 124 were screened positive (ie, with an elevated IRT level and 2 mutations in the CFTR gene), of whom 9 were found to be compound heterozygous for R117H.

To assess the clinical status of these 9 children, we constituted a control group composed of gender- and age- (±1 year) matched infants who were screened over the same period in Brittany and who carried the main CFTR genotype (F508del/F508del).

Assessment of Clinical Status
The clinical status at the last follow-up visit of the 9 children who are compound heterozygous for R117H and of the 9 control children was documented by the referring physicians. The compiled data included sociodemographic characteristics (gender, date of birth, date of the last visit), IRT and sweat chloride concentrations, anthropometric data (height and weight expressed as z scores, BMI), data on pancreatic function (presence of meconium ileus, pancreatic sufficiency or pancreatic insufficiency determined by the intake of pancreatic enzymes), data on pulmonary function usually measured from age 7 (forced expiratory volume in 1 second [FEV₁] and forced vital capacity [FVC], expressed as percentage of the predicted values), data on sputum microbiology obtained by CF cultures (colonization by typical CF pathogens such as Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia, etc), number of intravenous antibiotic cures, number of hospitalizations, and appearance of classical complications of CF.

The sequences of the IVS8 variant and of the TG repeat were obtained by the genetic laboratories.

Statistical Analysis
We assessed the frequency of the R117H variant in the cohort of newborns who screened positive for CF in Brittany since 1995. Then, we compared the clinical status of the children who were found to be compound heterozygous for this variant with that of the control group. Finally, we compared the frequency of R117H in the cohort of newborns screened positive for CF with that observed in a cohort of CF patients born in Brittany before the CFNS protocol enabled the detection of the R117H (1960–1994 period). Because of the small sample size, quantitative variables (expressed as mean ± SD) were compared by using the Mann-Whitney test, whereas qualitative variables (expressed as proportions) were compared by using a 2-tailed Fisher's exact test. A significance level of 5% was used for all the analyses.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Pilot newborn screening for CF was implemented in Brittany in 1989 and has enabled the detection of the R117H variant since 1995. From January 1, 1995, to December 31, 2004, 360466 newborns were screened for CF, of whom 124 had elevated IRT levels and 2 mutations in the CFTR gene (incidence: 1 in 2907). Nine of these children (7.3%) were compound heterozygous for R117H, which was only associated with the 7T_11TG haplotype. Their genotypes were F508del/R117H (n = 7), I507del/R117H (n = 1), or G551D/R117H (n = 1). The clinical outcome of these 9 children (5 boys and 4 girls) is presented in Table 1. One was lost to follow-up. At the time of this writing, the mean age of these children was 7.0 years (range: 4.0–10.9 years), and none of them had yet developed CF signs. The first sweat chloride concentration test results were negative for 4 children (<30 mEq/L) and borderline in the others (between 30 and 59 mEq/L). All these children are pancreatic sufficient. Their nutritional status and growth have seemed normal, with mean z scores for height and weight being close to zero (mean height z score: 0.6 [SD: 1.7]; mean weight z score: 0.2 [SD: 1.6]). Spirometric data, which were available for 2 children, have also seemed very good. Moreover, no classical complication of CF has been observed to date.

	DISCUSSION

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Since our CFNS protocol has enabled the detection of the R117H variant (ie, in 1995), 9 children compound heterozygous for R117H have been detected, which represents 7.3% of the CF children screened in Brittany over this period. R117H was only associated with the 7T form of the IVS8-nT variant and the 11TG sequence of the m(TG) repeat, which does not correspond to the lengths classically observed in the most expressive forms (12 or 13 TG).¹⁶ We show here that none of these children have yet developed any signs of CF, the oldest being >10 years of age. Those patients seemed to have better pulmonary function and lower hospitalization rates than a control group composed of gender- and age-matched newborns screened over the same period in Brittany. Moreover, no patient bearing a genotype including R117H-7T has yet been diagnosed in adulthood in our area.

However, manifestations of CF lung disease have been reported in some patients bearing R117H on a 7T background in 1 of their 2 CFTR mutated alleles.^18,21,22 In 2001, Massie et al¹⁸ reported data on a cohort of 38 patients compound heterozygous for R117H who were diagnosed through CFNS or on the basis of clinical signs. Close to 60% of these subjects carried R117H on a 7T background (n = 22). Most of them were identified by the CFNS program (n = 17) or through family testing (n = 3) and were still asymptomatic. Nevertheless, some pulmonary symptoms nonspecific for CF were reported in 4 of the 17 children detected through CFNS (recurrent bronchitis, persistent cough, asthma, etc).¹⁸ However, no data on sputum microbiology were available for the infants detected this way (sputum cultures were not performed). Only 2 patients were diagnosed on the basis of clinical signs in adulthood: bronchiectasis for a woman aged 27 years (sweat test result: 57 mmol/L) and daily cough and congenital bilateral absence of vas deferens in a 31-year-old man who was colonized by P aeruginosa (sweat test result: 95 and 102 mmol/L). The latter case shows that positive sweat test results can be observed in this genotype, and one cannot exclude the possibility that the sweat chloride concentration could increase with age in these patients. A recent article reported late diagnosis of CF in 2 elderly men carrying an R117H-7T haplotype heterozygous with either an N1303K or F508del mutation.²¹ The first patient, aged 61 years, presented with "a 7-month history of progressive weight loss, dyspnea, cough and fever"; his FEV₁ and FVC were 60% and 65% of the predicted values, respectively. This man was evaluated for infertility at the age of 27. The second patient, aged 64 years, presented with "symptoms of progressive shortness of breath and increased chronic sputum production." He was chronically colonized by P aeruginosa and reported suffering from persistent cough, sinusitis, and nasal polyps during childhood. Another article reported the delayed diagnosis of CF in a 63-year-old woman who carried an F508del/R117H genotype (the IVS8-nT sequence was not known). This woman presented with cough and dyspnea on exertion and was asymptomatic until that time.²² In 2000, Boyne et al²⁰ reported that 3 children screened at birth in the Trent region (United Kingdom) and who were F508del/R117H-7T compound heterozygous already had symptoms of lung disease. However, no detail was provided on either the age of these patients or their symptoms. Finally, in a recent abstract, Parad et al²⁴ reported that in the CFNS program in Massachusetts and New York, 19 children compound heterozygous for R117H were detected (18 were associated with the 7T variant) and that 3 of them had respiratory symptoms consistent with early CF. P aeruginosa was found in the cultures of 2 of the 9 children who had a sweat chloride concentration of <30 mEq/L. In these different reports, it would be important from a genetic point of view to know whether the entire CFTR gene has been analyzed in all these symptomatic patients to ensure the absence of another mutation in cis with the R117H-7T. Moreover, it would be interesting to know the length of the TG repeat sequence.

One can note that description in the literature of compound heterozygous CF patients bearing an R117H-7T haplotype who have progressed toward pulmonary signs of CF remains uncommon and contrast with the high frequency of this haplotype in CFNS programs. There could be underdiagnosis of late-presenting lung phenotypes because of decreased knowledge of CF diagnostic tests, sweat testing, and genotype among internists and clinicians who care for adults.

The high frequency of the R117H-7T haplotype identified by CFNS programs and the uncertain outcome of these asymptomatic children raise the question of whether this variant should be included in a CFTR mutation panel used for newborn screening. In our view, it should not be included for several reasons: because children are "labeled" at birth as having CF, families do not receive satisfactory genetic counseling, and physicians have difficulty managing such situations. It is not impossible that some of these asymptomatic children may develop manifestations of lung disease in adulthood. However, does the possible development of such signs in adulthood (perhaps not before the age of 60 years as has been reported^21,22) justify the formal diagnosis of classical CF at birth, with its consequences in terms of anxiety, possible discrimination for employment or insurance, and so forth?²⁵

In view of these data, we propose the withdrawal of the R117H variant from the panels of CFTR mutations used in newborn screening in light of the expanding implementation of CFNS worldwide. The R117H-5T haplotype is more obviously considered to be a disease-causing mutation¹⁷; therefore, it is not the overall frequency of the R117H variant that should be considered when deciding whether to include it in panels of mutations, but only the frequency of the R117H-5T haplotype. This haplotype is significantly less frequent than the threshold used for inclusion in such panels. Therefore, there is no reason to include it in kits for the detection of the 30 most common CFTR mutations observed in the CF population.

Let us recall that the aim of a CFNS program is the earlier diagnosis of classical forms of CF, and because the screening protocol includes the analysis of the most common CFTR mutations, it is of the utmost importance to include in this test only mutations that result in classical CF. This is particularly important in the near future, because many other countries will probably implement CFNS programs.

	ACKNOWLEDGMENTS

 
This work was supported by a grant from the association "Vaincre La Mucoviscidose" (project entitled "Registry of Molecular Epidemiology of Cystic Fibrosis in Brittany").

We thank the referring physicians who provided the data.

	FOOTNOTES

 
Accepted May 24, 2006.

Address correspondence to Claude Férec, MD, PhD, Inserm U613 Génétique Moléculaire et Génétique Épidémiologique, Laboratoire de Génétique Moléculaire, EFS-Bretagne, 46 Rue Félix Le Dantec, BP 62026, 29220 Brest Cedex 2, France. E-mail: claude.ferec{at}univ-brest.fr

The authors have indicated they have no financial relationships relevant to this article to disclose.

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