ABCMdb

PMID: 19880712

Thauvin-Robinet C, Munck A, Huet F, Genin E, Bellis G, Gautier E, Audrezet MP, Ferec C, Lalau G, Georges MD, Claustres M, Bienvenu T, Gerard B, Boisseau P, Cabet-Bey F, Feldmann D, Clavel C, Bieth E, Iron A, Simon-Bouy B, Costa C, Medina R, Leclerc J, Hubert D, Nove-Josserand R, Sermet-Gaudelus I, Rault G, Flori J, Leroy S, Wizla N, Bellon G, Haloun A, Perez-Martin S, d'Acremont G, Corvol H, Clement A, Houssin E, Binquet C, Bonithon-Kopp C, Alberti-Boulme C, Morris MA, Faivre L, Goossens M, Roussey M, Girod
The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.
J Med Genet. 2009 Nov;46(11):752-8. Epub 2009 Jun 29., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC7 p.Arg117His Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. Login to comment 2 ABCC7 p.Arg117His The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. Login to comment 3 ABCC7 p.Arg117His The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Login to comment 4 ABCC7 p.Arg117His Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. Login to comment 5 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His The allelic prevalences of R117H (pR117H), on either intron 8 T5 or T7 background, and F508del (pF508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. Login to comment 8 ABCC7 p.Arg117His The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). Login to comment 9 ABCC7 p.Arg117His The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Login to comment 10 ABCC7 p.Arg117His Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. Login to comment 13 ABCC7 p.Arg117His ABCC7 p.Arg117His The R117H mutation was initially considered as a mutation causing mild CF with pancreatic sufficiency,10 in keeping with a residual CFTR function supported by in vitro studies.11 R117H was then considered as predominantly associated with isolated CBAVD,4 12-14 generally in compound heterozygosity with F508del, the most frequent CF mutation. Login to comment 14 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Incidentally, the [R117H]+[F508del] genotype was observed in asymptomatic individuals.15 Phenotypic variability was mostly attributed to the presence of a polypyrimidine variant in the intron 8 acceptor splice site (T5 or T7) in cis with R117H, leading to R117H;T5 or R117H;T7 alleles. Login to comment 15 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His While the T7 variant is considered neutral, the T5 variant was shown to affect exon 9 splicing reducing the amount of CFTR protein, probably causing a more severe phenotype.15 16 It was therefore suggested to consider R117H as a CF mutation only in the context of the R117;T5 complex allele.17 However, early pulmonary manifestations were reported in patients carrying a severe CF mutation and R117H;T7.16 18-20 The implementation of systematic CF newborn screening (CFNBS) since 2002 in France, relying on determination of immunoreactive trypsinemia (IRT) and subsequent screening for 30 common CFTR mutations when IRT is above 65 mg/l, led to observe a much higher frequency of R117H;T7 in this population than in CF patients,21 adding further to the diagnostic dilemma.16 21-24 To assist with genetic counselling and to improve diagnostic practice, we implemented a large collaborative study to: (1) delineate the overall disease phenotype associated with R117H, and (2) evaluate the penetrance of CF in carriers of the [R117H]+[F508del] genotype-that is, the probability of individuals with this genotype to develop CF. Login to comment 16 ABCC7 p.Arg117His Another issue was to determine to what extent CFNBS methods select for [R117H]+[F508del] newborns. Login to comment 17 ABCC7 p.Arg117His ABCC7 p.Arg117His SUBJECTS AND METHODS Cross-sectional phenotypic study of individuals compound heterozygous for R117H and F508del All individuals known to the French CF Laboratory Network before 1 January 2008 who were heterozygous for R117H and F508del were included. Login to comment 18 ABCC7 p.Arg117His These were part of a larger record of all individuals carrying two CFTR mutations with R117H at least on one allele (manuscript in preparation). Login to comment 21 ABCC7 p.Arg117His Genotype data, including the intron 8 poly(T) variant in cis of R117H, were collected by the French CF Laboratory Network. Login to comment 25 ABCC7 p.Arg117His Epidemiological study in the French general population The allelic prevalence of R117H (pR117H) and F508del (pF508del) and 95% confidence interval (CI) were determined by allele counting in a sample of healthy adult individuals of the French general population. Login to comment 26 ABCC7 p.Arg117His Data were compiled from the French CF Laboratory Network as results of screening for about 30 frequent CFTR mutations (including R117H and F508del), performed between 2002 and 2006 in healthy partners of CF carriers or CF patients. Login to comment 28 ABCC7 p.Arg117His ABCC7 p.Arg117His Based on pR117H and pF508del and assuming Hardy-Weinberg equilibrium, the number of individuals expected to carry the [R117H]+[F508del] genotype in the French population was estimated to be p[R117H]+[F508del] = 26pR117H6pF508del. Login to comment 29 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Evaluation of the penetrance of CF in individuals with the [R117H]+[F508del] genotype The penetrance was defined as the observed number of [R117H]+[F508del] patients with clinical CF, divided by the expected number of individuals with the [R117H]+[F508del] genotype, calculated as defined above. Login to comment 30 ABCC7 p.Arg117His ABCC7 p.Arg117His Epidemiological record in newborns screened for CF To determine whether elevated IRT selects for [R117H]+[F508del] newborns, the number of [R117H]+[F508del] newborns identified through elevated IRT was compared with the total number of newborns expected to carry this genotype regardless of IRT, based on 26pR117H6pF508del. Login to comment 31 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Exhaustive data on newborns screened for CF from the 2002-2006 period, provided by the French Association for the Screening and Prevention of Infant Handicaps (AFDPHE), comprised: (1) the total number of newborns screened (NBS); (2) the number of newborns with elevated IRT; (3) the number of newborns with elevated IRT and the [R117H]+[F508del] genotype; (4) intron 8 poly(T) alleles in these children; (5) the number of newborns with elevated IRT and the F508del homozygous genotype. RESULTS Phenotypic description of patients compound heterozygous for R117H and F508del Among 278 individuals carrying two CFTR mutations with R117H at least on one allele, 193 [R117H]+[F508del] individuals were identified: 121 were referred for diagnosis request or positive family history and 72 were discovered through CFNBS (fig 1A). Login to comment 33 ABCC7 p.Arg117His The poly(T) genotype was known in 173/184 (94.0%) individuals: 166/173 (96.0%) carried T7 and seven (4.0%) T5 in cis with R117H. Login to comment 40 ABCC7 p.Arg117His The probabilities of occurrence of different symptoms with age were determined by Kaplan-Meyer analysis for the 166 [R117H;T7]+[F508del] patients (table 2). Login to comment 45 ABCC7 p.Arg117His Comprehensive CFTR gene analysis failed to identify a further mutation or large gene rearrangement in cis with R117H;T7 in this child. Login to comment 46 ABCC7 p.Arg117His ABCC7 p.Arg117His The low number of patients with the T5 variant precluded any comparison of the phenotypes associated with R117H;T5 and R117H;T7. Login to comment 48 ABCC7 p.Arg117His Of these, 151 carried one mutation (observed carrier frequency: 1/34.7), including 111 F508del (pF508del = 1.06%, 95% CI 0.87% to 1.27%) and 30 R117H (pR117H = 0.29%, 95% CI 0.19% to 0.41%) (fig 2A). Login to comment 50 ABCC7 p.Arg117His The intron 8 poly(T) variant was determined in 28/30 R117H carriers: all had the T7 variant. Login to comment 52 ABCC7 p.Arg117His ABCC7 p.Arg117His Based on these data, and in the absence of selective mortality associated with the [R117H;T7]+[F508del] genotype, the expected p[R117H;T7]+[F508del] is 1/17 470 (260.010660.0027, 95% CI 0.0001% to 0.032%), equivalent to 3650 individuals in the French population of 63 750 000 inhabitants. Login to comment 53 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Evaluation of the penetrance of CF in individuals with the [R117H;T7]+[F508del] genotype As R117H;T5 was not detected in the sample of 5245 healthy adult individuals, the penetrance was evaluated only for the [R117H;T7]+[F508del] genotype. Login to comment 54 ABCC7 p.Arg117His ABCC7 p.Arg117His While 3650 French individuals would be expected to carry the [R117H;T7]+[F508del] Figure 1 Cross-sectional phenotypic study in [R117H]+[F508del] compound heterozygous individuals. Login to comment 60 ABCC7 p.Arg117His ABCC7 p.Arg117His In total, 120 patients carrying the [R117H]+[F508del] genotype were recorded with cystic fibrosis (CF) or CFTR related disorders (CFTR-RD) symptoms, of whom 112 had the R117H;T7 allele. Login to comment 62 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Table 1 Clinical presentations in the 184 [F508del]+[R117H] compound heterozygous individuals, according to the poly(T) variant NBS children (n = 72) Non-NBS individuals (n = 112) Asymptomatic (No. of individuals) CF/CFTR-RD symptoms (No. of individuals) Asymptomatic (No. of individuals) CF/CFTR-RD symptoms (No. of individuals) R117H;T7 (n = 166) 47 14: 7 98: - 1 classical CF - 1 severe DB +CRS +CBAVD - 3 moderate pulmonary + nasopharyngeal - 1 severe DB+CRS - 7 moderate pulmonary - 2 DB+CBAVD - 3 nasopharyngeal - 2 DB - 7 moderate pulmonary+CRS+CBAVD - 9 moderate pulmonary+CBAVD - 4 moderate pulmonary+CRS - 1 moderate pulmonary+pancreatic+CBAVD - 7 moderate pulmonary - 6 CRS+CBAVD - 3 pancreatic+CBAVD - 1 CRS - 2 pancreatic - 52 isolated CBAVD R117H;T5 (n = 7) 2 1: 1 3: - 1 nasopharyngeal - 1 severe DB+CRS - 1 moderate pulmonary - 1 isolated CBAVD R117H;T? Login to comment 63 ABCC7 p.Arg117His { (n = 11) 6 2: 1 2: - 1 moderate pulmonary - 2 isolated CBAVD - 1 pancreatic Total 55 17 9 103 CBAVD, congenital bilateral absence of vas deferens; CRS, chronic rhinosinusitis; DB, disseminated bronchiectasis; NBS, newborn screened; Non-NBS, non-newborn screened (individuals who were not referred through newborn screening); R117H;T?, cases where the poly(T) variant was not determined or documented. genotype, only 112 (3.1%) with CF related symptoms were counted in the record of the French CF Laboratory Network, comprising 14 NBS and 98 non-NBS (table 1). Login to comment 67 ABCC7 p.Arg117His Based on the allele frequencies determined in the general population, 202 newborns with [R117H;T7]+[F508del] and 396 with [F508del]+[F508del] were expected among these newborns, irrespective of IRT values. Login to comment 69 ABCC7 p.Arg117His Of these, 52 were compound heterozygous for R117H and F508del (included in the 72 NBS children of the phenotypic study) and 332 homozygous for F508del. Login to comment 70 ABCC7 p.Arg117His All R117H alleles were found on the intron 8 T7 background (fig 2B). Login to comment 71 ABCC7 p.Arg117His Consequently, an Table 2 Probability of occurrence of clinical features at specific age in 166 French [F508del]+[R117H;T7] compound heterozygous individuals NBS children (n = 61) Non-NBS individuals (n = 105) No. of affected cases/no. of patients with available data Frequency (%) Penetrance of clinical features (%)* at age (years) No. of affected cases/no. of patients with available data Frequency (%) Penetrance of clinical features (%)* at age (years) 2 (99% CI) 2 (99% CI) 10 (99% CI) 30 (99% CI) Pulmonary symptoms 10/59 17 21 (10 to 42) 29/96 30 8 (3 to 19) 16 (8 to 28) 28 (17 to 42) Asthma 7/59 12 15 (6 to 37) 9/96 9 4 (1 to 14) 8 (4 to 20) 10 (4 to 21) Disseminated bronchiectasis 0/59 0 0 (NA) 7/96 7 0 (NA) 0 (NA) 5 (1 to 16) Nasopharyngeal symptoms 7/59 12 14 (5 to 37) 18/92 20 5 (2 to 16) 9 (4 to 21) 20 (11 to 34) Chronic sinusitis 7/59 12 14 (5 to 37) 13/92 14 5 (2 to 16) 10 (4 to 22) 15 (8 to 28) Nasal polyposis 0/59 0 0 (NA) 7/92 8 0 (NA) 0 (NA) 8 (3 to 21) Pancreatic symptoms 1/59 2 2 (0 to 20) 7/84 8 0 (NA) 0 (NA) 8 (3 to 23) Pancreatic insufficiency 1/59 2 2 (0 to 20) 2/84 2 0 (NA) 0 (NA) 2 (0 to 19) Chronic pancreatitis 0/59 0 0 (NA) 0/84 0 0 (NA) 0 (NA) 0 (NA) Acute pancreatitis 0/59 0 0 (NA) 5/84 6 0 (NA) 0 (NA) 4 (1 to 18) Staphylococcus aureus positive sputum/oropharyngeal cultures{ 19/49 39 37 (21 to 59) 10/37 27 0 (NA) 12 (3 to 36) 31 (13 to 63) Pseudomonas aeruginosa positive sputum/oropharyngeal cultures{ 6/49 12 13 (4 to 35) 1/39 3 0 (NA) 0 (NA) 0 (NA) NA, not applicable; NBS, newborn screened; non-NBS, individuals who were not referred through newborn screening. Login to comment 74 ABCC7 p.Arg117His For clarity, data regarding frequent mutations other than R117H and F508del are not indicated. Login to comment 77 ABCC7 p.Arg117His R117H;T? Login to comment 79 ABCC7 p.Arg117His Letter to JMG J Med Genet 2009;46:752-758. doi:10.1136/jmg.2009.067215 estimated 25.7% (95% CI 19.9% to 32.3%) of newborns carrying the [R117H;T7]+[F508del] genotype were identified through CFNBS, as compared with 83.8% (95% CI 79.8% to 87.3%) of F508del homozygous newborns (p,0.001). Login to comment 80 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His DISCUSSION A very low disease penetrance for R117H Because of the need for accuracy in genetic counselling, diagnosis and follow-up in newborns carrying R117H and a CF causing mutation, a national collaborative study in France was set up to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the [R117H]+[F508del] genotype. Login to comment 81 ABCC7 p.Arg117His The measured prevalence of F508del and R117H alleles in the French general population were very similar to those found in a US population (pR117H = 0.29% vs 0.3% and pF508del = 1.06% vs 1.2%).27 Moreover, according to the overall incidence of CF recently reassessed in France at 1/4136 and F508del frequency at 67.2% of CF chromosomes,21 pF508del in the general population would be expected to be 1.05%, which is also very close to the value we determined. Login to comment 83 ABCC7 p.Arg117His ABCC7 p.Arg117His The prevalences of F508del and R117H;T7 thus permitted the estimation of the number of individuals expected to carry the [R117H;T7]+[F508del] genotype in the French general population at 3650. Login to comment 84 ABCC7 p.Arg117His Our study revealed that only 3.1% (112/3650) of the individuals expected to carry the [R117H;T7]+[F508del] genotype have been tested for CFTR mutations because of clinical CF or CFTR-RD symptoms. Login to comment 93 ABCC7 p.Arg117His ABCC7 p.Arg117His Phenotypic variability is not fully explained by the IVS8 poly(T) variation The very low frequency of R117H;T5 in our population (but not T5 in isolation)31 has precluded any correlation between phenotype and the poly(T) variation in cis with R117H. Login to comment 94 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His The presence in our study of a severe CF case associated with R117H;T7 and the previously described overlap between patients carrying R117H;T5 and R117H;T7 show that the commonly cited correlation between phenotype and the poly(T) variant in cis with R117H has limitations.16 18-20 32 However, as R117H;T5 seems to be more frequent in Australian and UK populations and has been associated with a more severe phenotype than R117H;T7,15 16 determination of the poly(T) variant may still be recommended whenever R117H is detected and R117H;T5 cautiously be considered as a mild CF mutation. Login to comment 95 ABCC7 p.Arg117His Interestingly, five of the seven cases with R117H;T5 originated from Normandy, a north-western area of France which may have common ancestry with the UK. Login to comment 96 ABCC7 p.Arg117His To what extent does CFNBS detect newborns with R117H? Login to comment 97 ABCC7 p.Arg117His Based on pR117H;T7 and pF508del in the general population, one quarter of [R117H;T7]+[F508del] newborns appear to have elevated IRT and be identified through CFNBS, as compared with 83.7% of expected F508del homozygous newborns. Login to comment 99 ABCC7 p.Arg117His Furthermore, given the low disease penetrance detected in the present study for the [R117H;T7]+[F508del] genotype, we could hypothesise that only a minority of the newborns would develop clinical CF symptoms. Login to comment 100 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His These data show that the [R117H;T7]+[F508del] genotype is selected by CFNBS and provide further evidence that not only classical CF but also equivocal cases, CFTR-RD and a number of asymptomatic cases are selected by CFNBS.21 33 Implications for CFNBS and genetic counselling The pertinence of including R117H and mild CF mutations in CFNBS mutation panels has been debated because of the consequences of making a genetic diagnosis of CF in newborns who might not become symptomatic for years, if at all.16 19 22-24 26 34 35 Bearing in mind that the aim of CFNBS is the earlier diagnosis of classical forms of CF, our results provide strong Key points c The penetrance of classical cystic fibrosis (CF) for the [R117H;T7]+[F508del] genotype was evaluated at 0.03%, and that of severe CF in adulthood at 0.06%. Login to comment 101 ABCC7 p.Arg117His c It was estimated that only 3.1% of individuals expected to carry the [R117H;T7]+[F508del] genotype in the French population have been tested for CFTR mutations because of clinical CF or CFTR-RD symptoms or a positive family history. Login to comment 102 ABCC7 p.Arg117His c R117H on an intron 8 T7 background should be considered principally as a CFTR-RD-associated mutation with reduced penetrance. Login to comment 104 ABCC7 p.Arg117His c Withdrawal of R117H from CF mutation panels used for screening programmes should be considered. Login to comment 105 ABCC7 p.Arg117His arguments in favour of removing R117H from CFNBS mutation panels. Login to comment 106 ABCC7 p.Arg117His ABCC7 p.Arg117His However, as withdrawal of R117H would lead to further CFTR testing in NBS children with abnormal neonatal IRT and a positive or borderline sweat test, inclusion of R117H in a second-step panel would be a good compromise. Login to comment 107 ABCC7 p.Arg117His With regard to diagnosis and genetic counselling, R117H;T7 should be considered principally as a CFTR-RD associated mutation with reduced penetrance. Login to comment 109 ABCC7 p.Arg117His ABCC7 p.Arg117His Moreover, removal of R117H from CF mutation panels used for carrier screening should be considered, as healthy carriers of R117H could wrongly be considered CF carriers and prenatal diagnosis be improperly performed. Login to comment 111 ABCC7 p.Arg117His Author affiliations: 1 Centre de Ge´ne´tique, Hoˆpital d`Enfants, CHU de Dijon, Dijon, France; 2 AFDPHE, Paris, France; 3 French CF Care Centres, France; 4 CRCM - Service de gastro-ente´rologie-mucoviscidose et nutrition pe´diatriques, Hoˆpital Robert Debre´, APHP, Paris, France; 5 CRCM - Service de Pe´diatrie 1, Hoˆpital d`Enfants, CHU Dijon, Dijon, France; 6 Inserm U794 et Fondation Jean Dausset/CEPH, Paris, France; 7 INED, Paris, France; 8 Unite´ INSERM U866 CIE1, Faculte´ de me´decine de Dijon, CHU Dijon, Dijon, France; 9 French CF Laboratory Network, France; 10 Laboratoire de Ge´ne´tique Mole´culaire et d`Histocompatibilite´, CHU de Brest, Brest, France; 11 Poˆle de Biochimie et Biologie Mole´culaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France; 12 Laboratoire de Ge´ne´tique Mole´culaire, IURC, CHU de Montpellier, Montpellier, France; 13 Laboratoire de Biochimie-Ge´ne´tique, Hoˆpital Cochin, APHP, Paris, France; 14 Laboratoire de Biochimie Ge´ne´tique, Hoˆpital Robert Debre´, APHP, Paris, France; 15 Service de Ge´ne´tique Me´dicale, Laboratoire de Ge´ne´tique Mole´culaire, CHU Hoˆtel Dieu, Nantes, France; 16 Service d`Endocrinologie Mole´culaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France; 17 Laboratoire de Biochimie et Biologie Mole´culaire, Hoˆpital d`Enfants Armand Trousseau, APHP, Paris, France; 18 Laboratoire Pol Bouin, UF Biologie Cellulaire, Hoˆpital de la Maison Blanche, CHU de Reims, Reims, France; 19 Service de Ge´ne´tique Me´dicale, Hoˆpital Purpan, CHU de Toulouse, Toulouse, France; 20 Laboratoire de Ge´ne´tique Mole´culaire, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France; 21 Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France; 22 Service de Biochimie-Ge´ne´tique et Inserm U955 e´quipe 11, Groupe Henri Mondor-Albert Chenevier, APHP, Cre´teil, France; 23 CRCM - Service de Pneumologie, Hoˆpital Cochin, APHP, Paris, France; 24 CRCM - Service de Me´decine interne, Centre hospitalier Lyon sud, Pierre-Be´nite, France; 25 CRCM - Service de Pe´diatrie ge´ne´rale, Hoˆpital Necker-Enfants-Malades, APHP, Paris, France; 26 CRCM - Centre de Perharidy, Roscoff, France; 27 Service de Ne´onatologie, SIHCUS - CMCO, Schiltigheim, France; 28 CRCM - Service de pneumologie et immunoallergologie, CHRU de Lille, Lille, France; 29 CRCM - Clinique de pe´diatrie, CHRU de Lille, Lille, France; 30 CRCM Lyon Pe´diatrie, Groupement Hospitalier Lyon Est, Bron, France; 31 CRCM - Unite´ de transplantation thoracique, CHU Hoˆpital Guillaume et Rene´ Lae¨nnec, Nantes, France; 32 CRCM - Service de Pe´diatrie, CHI de Cre´teil, France; 33 CRCM - Service de pneumologie pe´diatrique, Hoˆpital d`Enfants Armand-Trousseau, APHP, Paris, France; 34 Centre d`Epide´miologie Clinique, Hoˆpital Robert Debre´, APHP, Paris, France; 35 Laboratoire de Diagnostic mole´culaire, Service de Me´decine Ge´ne´tique, Hoˆpitaux Universitaires, Geneva, Switzerland; 36 CRCM - De´partement de me´decine de l`enfant et de l`adolescent, CHU de Rennes - Hoˆpital Sud, Rennes, France Other members of the Collaborating Working Group on R117H: Referring molecular geneticists of the French CF Laboratory Network (34 molecular genetics laboratories): Dr A Bazin (Saint-Ouen l`Aumoˆne), Dr M Blayau (Rennes), Dr JP Bonnefont (Paris), Dr J Bouligand (Le Kremlin Biceˆtre), Dr M Che´ry (Nancy), Dr F Chevalier-Porst (Lyon), Dr JM Costa (Saint-Ouen l`Aumoˆne), Dr M Coude (Le Mans), Dr I Creveaux (Clermont-Ferrand), Dr V Dalstein (Reims), Dr A de Becdelie`vre (Cre´teil), Dr F Gerson (Nantes), Dr S Gobin-Limballe (Paris), Dr AM Gouget (Besanc¸on), Pr A Kitzis (Poitiers), Dr C Lagier-Tourenne (Strasbourg), Dr C Magdelaine (Limoges), Dr MC Malinge (Angers), Dr P Malzac (Marseille), Dr H Mittre (Caen), Dr V Petit (Epinal), Dr C Philippe (Vandoeuvre-les-Nancy), Dr P Ray (Grenoble), Dr M Raynaud (Tours), Dr C Ronsin (Ivry-sur-Seine), Dr S Schmitt (Nantes). 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