ABCMdb

PMID: 23378603

Thauvin-Robinet C, Munck A, Huet F, de Becdelievre A, Jimenez C, Lalau G, Gautier E, Rollet J, Flori J, Nove-Josserand R, Soufir JC, Haloun A, Hubert D, Houssin E, Bellis G, Rault G, David A, Janny L, Chiron R, Rives N, Hairion D, Collignon P, Valeri A, Karsenty G, Rossi A, Audrezet MP, Ferec C, Leclerc J, Georges Md, Claustres M, Bienvenu T, Gerard B, Boisseau P, Cabet-Bey F, Cheillan D, Feldmann D, Clavel C, Bieth E, Iron A, Simon-Bouy B, Izard V, Steffann J, Viville S, Costa C, Drouineaud V, Fauque P, Bi
CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
J Med Genet. 2013 Apr;50(4):220-7. doi: 10.1136/jmedgenet-2012-101427. Epub 2013 Feb 1., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Arg117His ABCC7 p.Arg117His ORIGINAL ARTICLE CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders Christel Thauvin-Robinet,1,2 Anne Munck,3,4 Fr&#e9;d&#e9;ric Huet,2,3,5 Alix de Becdeli&#e8;vre,6 Cl&#e9;ment Jimenez,7 Guy Lalau,8 Elodie Gautier,9,10 Jacques Rollet,11 Jean Flori,12 Rapha&#eb;lle Nov&#e9;-Josserand,13 Jean-Claude Soufir,14 Alain Haloun,15 Dominique Hubert,16 Elise Houssin,3 Gil Bellis,17 Gilles Rault,18 Albert David,19 Laurent Janny,20 Rapha&#eb;l Chiron,21 Nathalie Rives,22 Dominique Hairion,23 Patrick Collignon,24 Antoine Valeri,25 Gilles Karsenty,26 Annick Rossi,27 Marie-Pierre Audr&#e9;zet,28 Claude F&#e9;rec,28 Julie Leclerc,8 Marie des Georges,29 Mireille Claustres,29 Thierry Bienvenu,30 B&#e9;n&#e9;dicte G&#e9;rard,31 Pierre Boisseau,32 Fa&#ef;za Cabet-Bey,33 David Cheillan,3,34 Delphine Feldmann,35 Christine Clavel,36 Eric Bieth,37 Albert Iron,38 Brigitte Simon-Bouy,39 Vincent Izard,40 Julie Steffann,41 St&#e9;phane Viville,42 Catherine Costa,6 V&#e9;ronique Drouineaud,7 Patricia Fauque,2,7 Christine Binquet,9 Claire Bonithon-Kopp,9 Mike A Morris,43 Laurence Faivre,1,2 Michel Goossens,6 Michel Roussey,3,44 Emmanuelle Girodon,6 the collaborating working group on p.Arg117His b8; Additional material is published online only. Login to comment 4 ABCC7 p.Arg117His ABSTRACT Background The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. Login to comment 5 ABCC7 p.Arg117His Methods Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. Login to comment 6 ABCC7 p.Arg117His Results 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. Login to comment 12 ABCC7 p.Arg117His Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. Login to comment 13 ABCC7 p.Arg117His Conclusions Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Login to comment 20 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His The c.350G>A (p.Arg117His, R117H) mutation, though initially described in CF patients,5 has been considered predominantly associated with CBAVD.6-9 Phenotypic variability was mostly attributed to the presence of a polymorphic intronic polyT variant, c.1210-12T(5) or T(7) in cis with p.Arg117His (ie, T5 or T7 on the same chromosome as p.Arg117His). Login to comment 21 ABCC7 p.Arg117His While the T7 variant is considered neutral, the T5 variant in cis 220 with p.Arg117His has been associated with a more severe outcome. Login to comment 22 ABCC7 p.Arg117His 11 The recent observation of a high frequency of p. Arg117His in newborns screened for CF has reinforced diagnostic and genetic counselling dilemmas,12 even for CBAVD couples because of reproductive concerns. Login to comment 23 ABCC7 p.Arg117His ABCC7 p.Arg117His Epidemiological data from a large collaborative French survey on this mutation have already identified very low penetrance of classical CF in individuals carrying p.Arg117His in cis with T7 and the most frequent CF mutation, c.1521_1523del (p.Phe508del, F508del), with penetrance estimated at 0.03%.13 The aim of the present study was to focus on and detail phenotype and genotype data in CBAVD patients who carried two CFTR mutations with p.Arg117His on at least one allele, and to document the outcomes of assisted reproduction techniques (ART), and prenatal and preimplantation diagnoses (PND and PGD) for the couples, with a view to improving practices for follow-up and genetic counselling. Login to comment 24 ABCC7 p.Arg117His SUBJECTS AND METHODS Clinical and genotype-phenotype correlation studies A retrospective cohort study was initiated by the French CF laboratory network to collect phenotype and genotype data of all individuals with two CFTR mutations including p.Arg117His on at least one allele, identified from 1990 until 1 January 2008. Login to comment 25 ABCC7 p.Arg117His CFTR mutations in trans of p.Arg117His (ie, on the other chromosome) were classified by their potential for causing disease (A: CF-causing; B: associated with CFTR-RD; C: no clinical consequences; D: unknown or uncertain clinical relevance).2 4 Genotype data also included the polyT variant at c.1210-12T(5_9). Login to comment 39 ABCC7 p.Arg117His RESULTS A total of 278 individuals with two CFTR mutations including at least one p.Arg117His were collected. Login to comment 42 ABCC7 p.Arg117His The overall cohort Genotype description In the 278 individuals, 44 different mutations were associated with p.Arg117His. Login to comment 43 ABCC7 p.Arg117His CF mutations (class A) were present in trans of p.Arg117His in nearly 90% of individuals, including c.1521_1523del (p.Phe508del, F508del) in 121 individuals (67%). Login to comment 44 ABCC7 p.Trp1282* ABCC7 p.Gly542* The other mutations consisted of c.3846G>A (p.Trp1282*, W1282X) (2%), c.1624G>T (p.Gly542*, G542X) (2%), c.262_263del (394delTT) (2%), c.1585-1G>A (1717-1G>A) (2%) and other mutations (25%). Login to comment 45 ABCC7 p.Arg117His One individual was p.Arg117His homozygous. Login to comment 46 ABCC7 p.Arg117His No significant clinical difference was noticed between patients according to the mutation in trans of p.Arg117His. Login to comment 47 ABCC7 p.Arg117His Among the 172 patients with a documented polyT variant, only five carried T5 in cis with p.Arg117His, two males and three females, including one sibship (see online supplementary data table A). Login to comment 62 ABCC7 p.Arg117His By contrast, four other men without CBAVD spontaneously fathered children: three carried a severe CF mutation and one had a mild, CFTR-RD mutation in trans of p. Arg117His. Login to comment 69 ABCC7 p.Arg117His No significant clinical difference was noticed between CBA VD patients according to the mutation in trans of p.Arg117His. Login to comment 70 ABCC7 p.Arg117His No significant difference related to classification of the mutation in trans of p.Arg117His was noticed between patients with isolated CBAVD and other patients. Login to comment 84 ABCC7 p.Arg117His Table 1 Probability of the occurrence of clinical features at a specific age in 166 compound heterozygous individuals carrying p.Arg117His Total cohort n=166 CBAVD patients n=125 No. Login to comment 96 ABCC7 p.Arg117His Eight children were born, including four who were compound heterozygous for p.Arg117His and one severe CF mutation. Login to comment 97 ABCC7 p.Arg117His They are healthy so far. DISCUSSION We have recently shown that the penetrance of classical CF in individuals carrying p.Arg117His on a T7 background and p. Phe508del is very low, at 0.03%, and that only 3.1% of individuals expected to carry this genotype have come to clinical attention and been tested for CFTR mutations.13 The objective of the present study was to describe the overall phenotype Table 2 Fertility data in the 40 couples followed in assisted medical reproduction centres with available data n Per puncture Per fresh transfer Mean Std Mean Std Injected ovocytes 738 8.4 4.7 Fertilised ovocytes 426 4.5 4.5 Embryos 361 4.2 4.2 Fertilisation rate* - 51% 29% Fresh cycle outcomes Punctures with fresh transfers 78 85% 36% Transferred embryos 143 1.6 1.0 Clinical pregnancy rate 26 29% 45% 34% 48% Miscarriage rateߤ 5 6% 25% Delivery rate 19 22% 42% 26% 44% Frozen embryos 82 0.9 1.9 *Fertilisation rate=number of embryos/number of ovocytes injected. Login to comment 103 ABCC7 p.Arg117His Thauvin-Robinet C, et al. J Med Genet 2013;50:220-227. doi:10.1136/jmedgenet-2012-101427 223 Genotype-phenotype correlations associated with p.Arg117His plus a second CFTR mutation, in order to improve practices for the diagnosis and follow-up of patients and improve genetic counselling, in particular, for couples requiring assisted reproduction. Login to comment 104 ABCC7 p.Arg117His ABCC7 p.Arg117His Indeed, p.Arg117His was shown to be the third most frequent mutation found in French CBAVD patients.8 9 The frequency of the T5 variant in cis with p.Arg117His was much lower in France than that reported in Australian and UK populations,10 11 thus preventing any correlation between phenotype and polyT variation in the present study. Login to comment 105 ABCC7 p.Arg117His Our conclusions can thus be drawn only for populations in whom p. Arg117His on a T7 background is predominant. Login to comment 107 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His As nearly 90% of patients carried a CF mutation in trans of p.Arg117His, it is hypothesized that compound heterozygosity for p.Arg117His on a T7 background and another mild mutation would predominantly be associated with no obvious CFTR disease.13 An overall mild phenotype with predominant CBAVD in males and a low penetrance in females We present the genotypes and phenotypes of 166/179 individuals carrying two CFTR mutations with p.Arg117His on at least one allele, which is the largest cohort described to date. Login to comment 113 ABCC7 p.Arg117His Late presentation of CF has previously been reported in the literature, in two males at 61 and 64 years of age, carrying p.Arg117His in cis with T7 and presenting with infertility and severe bronchiectasis.16 Thus, a complete initial evaluation and regular follow-up should be proposed in CBAVD patients, who might develop pulmonary symptoms a long time after the genetic analysis requested for assisted reproduction purposes. Login to comment 116 ABCC7 p.Arg117His All the patients with pancreatic symptoms had the T7 allele in cis with p.Arg117His. Login to comment 119 ABCC7 p.Arg117His ABCC7 p.Arg117His These observations question the positive diagnostic value of sweat testing in individuals carrying p.Arg117His in cis with T7, as previously reported.20 Males and fertility CFTR-RD is not the rule in individuals carrying p.Arg117His plus a CF mutation, as previously demonstrated13 and exemplified by the four healthy men of the study who fathered spontaneously. Login to comment 121 ABCC7 p.Arg117His (Phe508del);(Arg117His) p.Phe508del 1998 Offer of sperm donor na CF or CFTR-RD p. Login to comment 122 ABCC7 p.Arg117His (Phe508del);(Arg117His) p.Phe508del 2000 2001: PND leading to twin pregnancy 2005: PGD leading to twin pregnancy 2 2* CF or CFTR-RD p. Login to comment 123 ABCC7 p.Arg117His (Phe508del);(Arg117His) p.Phe508del 2004 2005: PGD, no pregnancy - CF or CFTR-RD c. Login to comment 125 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu (Ala455Glu);( Arg117His) p.Gly551Asp 1995 No spontaneous pregnancy and no in vitro fertilisation - CF or CFTR-RD p. Login to comment 126 ABCC7 p.Arg117His ABCC7 p.Leu206Trp ABCC7 p.Ser1235Arg (Leu206Trp);( Arg117His) p.Ser1235Arg 2000 2 ICSI cycles, no pregnancy Offer of donor sperm - CFTR-RD p. Login to comment 127 ABCC7 p.Arg117His (Phe508del);(Arg117His) c.3528del 2001 2001-2006: 6 preimplantation cycles, 7 transferred embryos, 3 pregnancies (including 1 triple) 2 CF or CFTR-RD Genotypes are written according to HGVS Human Genome Variation Society (HGVS) recommendations. Login to comment 128 ABCC7 p.Arg117His ABCC7 p.Ser1235Arg Notably, c.350G>A corresponds to p.Arg117His and c.3705T>G to p.Ser1235Arg. Login to comment 129 ABCC7 p.Arg117His All CBAVD patients carried the T7 variant in cis with p.Arg117His. Login to comment 131 ABCC7 p.Arg117His (Phe508del);(Arg117His) genotype. Login to comment 136 ABCC7 p.Arg117His Nevertheless, given that CBAVD is the most frequent symptom observed in our cohort, we suggest that male individuals carrying p.Arg117His in combination with another CFTR mutation and referred for a family study, or respiratory or pancreatic symptoms be offered fertility investigations in an ART clinic, according to the clinical context and the patients` wishes. Login to comment 139 ABCC7 p.Arg117His Based on the recent reclassification of p. Arg117His in cis with T7 as a CFTR-RD mutation, it should not be considered for either cascade testing in relatives, or for a risk of classical CF in offspring. Login to comment 143 ABCC7 p.Arg117His On the other hand, once CBAVD patients are found to carry a CF-causing mutation in trans of p.Arg117His (90% of cases in our series), their partner should be offered testing for frequent CF mutations. Login to comment 147 ABCC7 p.Arg117His Because of the increased risk of obtaining embryos carrying two CF-causing mutations, it could be discussed to implant embryos with a CFTR-RD genotype in a PGD process, as was the case for two couples in our series who associated p. Arg117His and a CF mutation. Login to comment 149 ABCC7 p.Arg117His In conclusion, our results indicate the need for a complete initial clinical evaluation in patients with at least one p. Arg117His mutation, especially in CBAVD patients who may be free of respiratory symptoms at the time of the genetic analysis requested for assisted reproduction purposes, and for appropriate genetic counselling. Login to comment 152 ABCC7 p.Arg117His Thauvin-Robinet C, et al. J Med Genet 2013;50:220-227. doi:10.1136/jmedgenet-2012-101427 225 Genotype-phenotype correlations 20 Laboratoire de Biologie de la Reproduction et CECOS, CHU Estaing, Clermont-Ferrand, France 21 CRCM-Service de P&#e9;diatrie, CHU Montpellier, Montpellier, France 22 EA 4308 &#ab; Spermatog&#e9;n&#e8;se et qualit&#e9; du sperme m&#e2;le &#bb;, IFRMP23-IHU Rouen Normandie, Laboratoire de Biologie de la Reproduction-CECOS, CHU Rouen, Rouen, France 23 Laboratoire d`analyses m&#e9;dicales Giorgetti, Marseille, France 24 G&#e9;n&#e9;tique M&#e9;dicale, CH Toulon, Toulon, France 25 Service d`Urologie, CHU Brest, Brest, France 26 Chirurgie Urologique, H&#f4;pital Sainte-Marguerite, APHM, Marseille, France 27 EFS-Normandie, Bois-Guillaume, France 28 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire et d`Histocompatibilit&#e9;, CHU de Brest, Brest, France 29 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, IURC, CHU de Montpellier, Montpellier, France 30 Laboratoire de Biochimie-G&#e9;n&#e9;tique, H&#f4;pital Cochin, APHP, Paris, France 31 Laboratoire de Biochimie G&#e9;n&#e9;tique, H&#f4;pital Robert Debr&#e9;, APHP, Paris, France 32 Service de G&#e9;n&#e9;tique M&#e9;dicale, Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, CHU H&#f4;tel Dieu, Nantes, France 33 Service d`Endocrinologie Mol&#e9;culaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France 34 Service des Maladies H&#e9;r&#e9;ditaires du M&#e9;tabolisme et D&#e9;pistage N&#e9;onatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France 35 Laboratoire de Biochimie et Biologie Mol&#e9;culaire, H&#f4;pital d`Enfants Armand Trousseau, APHP, Paris, France 36 CHU Reims, Inserm UMRS 903, Laboratoire Pol Bouin, UF Biologie Cellulaire, H&#f4;pital de la Maison Blanche, Reims, France 37 Service de G&#e9;n&#e9;tique M&#e9;dicale, H&#f4;pital Purpan, Toulouse, France 38 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, Service de G&#e9;n&#e9;tique M&#e9;dicale, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France 39 Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France 40 Service d`Urologie, CHU Bic&#ea;tre, APHP, France 41 Unit&#e9; INSERM U781, Universit&#e9; Paris-Descartes, Facult&#e9; de M&#e9;decine, Service de G&#e9;n&#e9;tique M&#e9;dicale, AP-HP, Paris, France 42 Unit&#e9; de diagnostic pr&#e9;-implantatoire, Centre M&#e9;dico-Chirurgical et Obst&#e9;trical (SIHCUS-CMCO), Schiltigheim, France 43 Laboratoire de Diagnostic mol&#e9;culaire, Service de M&#e9;decine G&#e9;n&#e9;tique, H&#f4;pitaux Universitaires de Gen&#e8;ve, Gen&#e8;ve, Switzerland 44 CRCM-D&#e9;partement de m&#e9;decine de l`enfant et de l`adolescent, CHU de Rennes -H&#f4;pital Sud, Rennes, France Collaborators working group on p.Arg117His Referring molecular geneticists of the French CF laboratory network (34 molecular genetics laboratories): Dr A Bazin (Saint-Ouen l`Aum&#f4;ne), Dr M Blayau (Rennes), Dr JP Bonnefont (Paris), Dr J Bouligand (Le Kremlin Bic&#ea;tre), Dr M Ch&#e9;ry (Nancy), Dr F Chevalier-Porst (Lyon), Dr JM Costa (Saint-Ouen l`Aum&#f4;ne), Dr M Coude (Le Mans), Dr I Creveaux (Clermont-Ferrand), Dr V Dalstein (Reims), Dr F Gerson (Nantes), Dr S Gobin-Limballe (Paris), Dr AM Gouget (Besan&#e7;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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