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  • The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening

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Letter to JMG
The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening
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  1. C Thauvin-Robinet1,3,
  2. A Munck2,3,4,
  3. F Huet2,3,5,
  4. E Génin6,
  5. G Bellis7,
  6. E Gautier8,
  7. M-P Audrézet9,10,
  8. C Férec9,10,
  9. G Lalau9,11,
  10. M Des Georges9,12,
  11. M Claustres9,12,
  12. T Bienvenu9,13,
  13. B Gérard9,14,
  14. P Boisseau9,15,
  15. F Cabet-Bey9,16,
  16. D Feldmann9,17,
  17. C Clavel9,18,
  18. E Bieth9,19,
  19. A Iron9,20,
  20. B Simon-Bouy9,21,
  21. C Costa9,22,
  22. R Medina22,
  23. J Leclerc9,11,
  24. D Hubert3,23,
  25. R Nové-Josserand3,24,
  26. I Sermet-Gaudelus3,25,
  27. G Rault3,26,
  28. J Flori27,
  29. S Leroy3,28,
  30. N Wizla3,29,
  31. G Bellon3,30,
  32. A Haloun3,31,
  33. S Perez-Martin3,5,
  34. G d’Acremont3,32,
  35. H Corvol3,33,
  36. A Clément3,33,
  37. E Houssin2,
  38. C Binquet8,
  39. C Bonithon-Kopp8,
  40. C Alberti-Boulmé34,
  41. M A Morris35,
  42. L Faivre1,
  43. M Goossens9,22,
  44. M Roussey2,3,36
  1. 1
    Centre de Génétique, Hôpital d’Enfants, CHU de Dijon, Dijon, France
  2. 2
    AFDPHE, Paris, France
  3. 3
    French CF Care Centres, France
  4. 4
    CRCM - Service de gastro-entérologie-mucoviscidose et nutrition pédiatriques, Hôpital Robert Debré, APHP, Paris, France
  5. 5
    CRCM – Service de Pédiatrie 1, Hôpital d’Enfants, CHU Dijon, Dijon, France
  6. 6
    Inserm U794 et Fondation Jean Dausset/CEPH, Paris, France
  7. 7
    INED, Paris, France
  8. 8
    Unité INSERM U866 CIE1, Faculté de médecine de Dijon, CHU Dijon, Dijon, France
  9. 9
    French CF Laboratory Network, France
  10. 10
    Laboratoire de Génétique Moléculaire et d’Histocompatibilité, CHU de Brest, Brest, France
  11. 11
    Pôle de Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France
  12. 12
    Laboratoire de Génétique Moléculaire, IURC, CHU de Montpellier, Montpellier, France
  13. 13
    Laboratoire de Biochimie-Génétique, Hôpital Cochin, APHP, Paris, France
  14. 14
    Laboratoire de Biochimie Génétique, Hôpital Robert Debré, APHP, Paris, France
  15. 15
    Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, CHU Hôtel Dieu, Nantes, France
  16. 16
    Service d’Endocrinologie Moléculaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France
  17. 17
    Laboratoire de Biochimie et Biologie Moléculaire, Hôpital d’Enfants Armand Trousseau, APHP, Paris, France
  18. 18
    Laboratoire Pol Bouin, UF Biologie Cellulaire, Hôpital de la Maison Blanche, CHU de Reims, Reims, France
  19. 19
    Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France
  20. 20
    Laboratoire de Génétique Moléculaire, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France
  21. 21
    Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France
  22. 22
    Service de Biochimie-Génétique et Inserm U955 équipe 11, Groupe Henri Mondor-Albert Chenevier, APHP, Créteil, France
  23. 23
    CRCM - Service de Pneumologie, Hôpital Cochin, APHP, Paris, France
  24. 24
    CRCM - Service de Médecine interne, Centre hospitalier Lyon sud, Pierre-Bénite, France
  25. 25
    CRCM - Service de Pédiatrie générale, Hôpital Necker-Enfants-Malades, APHP, Paris, France
  26. 26
    CRCM - Centre de Perharidy, Roscoff, France
  27. 27
    Service de Néonatologie, SIHCUS – CMCO, Schiltigheim, France
  28. 28
    CRCM - Service de pneumologie et immunoallergologie, CHRU de Lille, Lille, France
  29. 29
    CRCM - Clinique de pédiatrie, CHRU de Lille, Lille, France
  30. 30
    CRCM Lyon Pédiatrie, Groupement Hospitalier Lyon Est, Bron, France
  31. 31
    CRCM - Unité de transplantation thoracique, CHU Hôpital Guillaume et René Laënnec, Nantes, France
  32. 32
    CRCM - Service de Pédiatrie, CHI de Créteil, France
  33. 33
    CRCM - Service de pneumologie pédiatrique, Hôpital d’Enfants Armand-Trousseau, APHP, Paris, France
  34. 34
    Centre d’Epidémiologie Clinique, Hôpital Robert Debré, APHP, Paris, France
  35. 35
    Laboratoire de Diagnostic moléculaire, Service de Médecine Génétique, Hôpitaux Universitaires, Geneva, Switzerland
  36. 36
    CRCM - Département de médecine de l’enfant et de l’adolescent, CHU de Rennes - Hôpital Sud, Rennes, France
  1. Correspondence to Dr C Thauvin-Robinet, Centre de Génétique, Hôpital d’Enfants, 10, bd Maréchal de Lattre de Tassigny, BP 77 908, 21079 Dijon cedex, France; christel.thauvin{at}chu-dijon.fr

Abstract

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice.

Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. 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. The disease phenotype was predominantly mild; one child had classical CF, and three adults’ severe pulmonary symptoms. In 5245 healthy adults, pF508del was 1.06%, pR117H;T7 0.27% and pR117H;T5<0.01%. 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%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%.

Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

https://doi.org/10.1136/jmg.2009.067215

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    Footnotes

    • For numbered affiliations see end of article

    • 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’Aumône), Dr M Blayau (Rennes), Dr JP Bonnefont (Paris), Dr J Bouligand (Le Kremlin Bicêtre), Dr M Chéry (Nancy), Dr F Chevalier-Porst (Lyon), Dr JM Costa (Saint-Ouen l’Aumône), Dr M Coude (Le Mans), Dr I Creveaux (Clermont-Ferrand), Dr V Dalstein (Reims), Dr A de Becdelièvre (Créteil), Dr F Gerson (Nantes), Dr S Gobin-Limballe (Paris), Dr AM Gouget (Besançon), 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). Referring physicians who provided the clinical data (47 CF care centres): Pr M Abely (Reims), Dr M Albert (Poissy), Dr L Bassinet (Créteil), Dr S Bonnefoy (Paris), Dr G Bourouillou (Toulouse), Dr F Bremont (Toulouse), Dr MP Brechard (Marseille), Dr C Chardot (Le Kremlin Bicêtre), Dr MC Chevalier (Le Mans), Dr J Chiesa (Nìmes), Dr R Chiron (Montpellier), Dr A Ciolkovitch (Agen), Dr P Collignon (Toulon), Dr F Counil (Montpellier), Dr P Costa (Nìmes), Dr A David (Nantes), Dr V David (Nantes), Pr C Delacourt (Créteil), Dr D Delafontaine (Paris), Dr F Delepoulle (Dunkerque), Dr MA Delrue (Bordeaux), Dr E Deneuville (Rennes), Dr J Derelle (Nancy), Pr B Desrues (Rennes), Dr S Dominique (Rouen), Dr AL Fanton (Dijon), Dr E Flori (Strasbourg), Dr P Foucaud (Le Chesnay), Dr S Froment (Tours), Dr D Gaillard (Reims), Pr P Giacomini (Reims), Dr C Gambert (Poitiers), Dr E Gautier (Neuilly), Dr JL Ginies (Angers), Dr E Ginglinger (Mulhouse), Dr F Gottrand (Lille), Dr A Guichet (Angers), Dr M Guillot (Lisieux), Dr D Hairion (Marseille), Dr MC Heraud (Clermont-Ferrand), Dr E Houriez-Bertolo (Nancy), Dr V Izard (Le Kremlin-Bicêtre), Dr L Janny (Clermont-Ferrand), Dr E Jeandidier (Mulhouse), Dr H Journel (Vannes), Dr G Karsenty (Marseille), Dr Labarière, Dr K Lahsinat (Elboeuf), Dr S Langlais (Montereau), Dr J Languepin (Limoges), Dr M Laurans (Caen), Dr D Lauton (Montpellier), Dr V Layet (Le Havre), Dr M Le Bourgeois (Paris), Pr D Le Lannou (Rennes), Pr H Lejeune (Lyon), Pr G Lenoir (Paris), Dr F Lestrade (Metz), Dr C Llerena (Grenoble), Dr B Marc (Béziers), Dr S Marchand (Tours), Pr C Marguet (Rouen), Dr O Marteletti (Lens), Dr G Massat (Toulouse), Dr L Mely (Giens), Dr C Menetrey (Limoges), Dr V Moisan-Petit (Vannes), Dr S Montcouquiol (Nancy), Dr L Moreau (Nice), Pr S Odent (Rennes), Dr M Pagenault (Rennes), Pr P Parent (Brest), Dr JC Pautard (Amiens), Dr MO Peter (Mulhouse), Dr D Pierre (Nancy), Dr I Pin (Grenoble), Dr G Plessis (Caen), Dr S Ramel (Roscoff), Dr F Rembert-Sagot (Dunkerque), Dr N Rives (Rouen), Dr J Rollet (Lyon), Dr A Rossi (Bois Guillaume), Dr C Roux (Besançon), Pr D Royere (Tours), Dr A Sardet (Lens), Pr J Sarles (Marseille), Pr JP Siffroi (Paris), Pr JP Saulnier (Poitiers), Dr J Sehabiague (Agen), Dr PM Sinet (Paris), Pr JC Soufir (le Kremlin-Bicêtre), Dr E Tassin (Le Chesnay), Dr F Terro (Limoges), Pr D Turck (Lille), Pr A Valeri (Brest), Dr MV Vodoff (Mulhouse), Dr L Wagner (Nìmes), Dr L Weiss (Strasbourg).

    • Funding This work was supported by a grant from the University Hospital of Dijon, the “Conseil Régional de Bourgogne” and the French CF Foundation “Vaincre La Mucoviscidose”.

    • Competing interests None.

    • Patient consent Not required.

    • Provenance and Peer review Not commissioned; externally peer reviewed.