ABCMdb

PMID: 19843100

Burgel PR, Fajac I, Hubert D, Grenet D, Stremler N, Roussey M, Siret D, Languepin J, Mely L, Fanton A, Labbe A, Domblides P, Vic P, Dagorne M, Reynaud-Gaubert M, Counil F, Varaigne F, Bienvenu T, Bellis G, Dusser D
Non-classic cystic fibrosis associated with D1152H CFTR mutation.
Clin Genet. 2010 Apr;77(4):355-64. Epub 2009 Oct 15., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC7 p.Asp1152His All rights reserved (c) 2009 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2009.01294.x Short Report Non-classic cystic fibrosis associated with D1152H CFTR mutation Burgel P-R, Fajac I, Hubert D, Grenet D, Stremler N, Roussey M, Siret D, Languepin J, Mely L, Fanton A, Labb´e A, Domblides P, Vic P, Dagorne M, Reynaud-Gaubert M, Counil F, Varaigne F, Bienvenu T, Bellis G, Dusser D. Login to comment 2 ABCC7 p.Asp1152His Non-classic cystic fibrosis associated with D1152H CFTR mutation. Clin Genet 2010: 77: 355-364. Login to comment 3 ABCC7 p.Asp1152His (c) John Wiley & Sons A/S, 2009 Background: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. Login to comment 4 ABCC7 p.Asp1152His Methods: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Login to comment 6 ABCC7 p.Asp1152His Results: Forty-two subjects with D1152H alleles were identified. Login to comment 8 ABCC7 p.Asp1152His Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Login to comment 9 ABCC7 p.Asp1152His Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Login to comment 10 ABCC7 p.Asp1152His Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Login to comment 11 ABCC7 p.Asp1152His Estimated rates of decline in forced expiratory volume in 1 s (FEV1) were lower in D1152H subjects vs PI CF subjects (p < 0.05). Login to comment 12 ABCC7 p.Asp1152His None of the D1152H subjects identified since 1999 had died or required lung transplantation. Login to comment 13 ABCC7 p.Asp1152His Conclusions: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival. Login to comment 14 ABCC7 p.Asp1152His P-R Burgela, I Fajaca, D Huberta, D Grenetb, N Stremlerc, M Rousseyd, D Sirete , J Languepinf , L Melyg , A Fantonh, A Labb ´ei, P Domblidesj, P Vick, M Dagorned, M Reynaud-Gaubertl , F Counilm, F Varaignen, T Bienvenua, G Belliso and D Dussera aH ˆopital Cochin, APHP, Universit ´e Paris Descartes, Paris, France, bH ˆopital Foch, Suresnes, France, cCHU de la Timone, Marseille, France, dCHU de Rennes, Universit ´e Rennes 1, France, eCH de St Nazaire, St Nazaire, France, fCHU de Limoges, Limoges, France, gCRCM du Var, Giens, France, hCHU le Bocage, Universit ´e de Bourgogne, Dijon, France, iCHRU de Clermont Ferrand, Clermont Ferrand, France, jCHU de Bordeaux, Bordeaux, France, kCentre Hospitalier de Cornouaille, Quimper, France, l CHU Sud Sainte Marguerite, Marseille, France, m CHU Arnaud de Villeneuve, Montpellier, France, n H ˆopital Bretonneau, Tours, France, and o Institut National d`Etudes D ´emographiques, Paris, France Key words: bronchiectasis - congenital absence of the vas deferens - cystic fibrosis transmembrane conductance regulator - D1152H - exocrine pancreatic insufficiency Corresponding author: Pierre-R ´egis Burgel, MD, PhD, Service de Pneumologie, H ˆopital Cochin, 27 rue du Faubourg St Jacques, 75679 Paris Cedex 14, France. Login to comment 20 ABCC7 p.Asp1152His D1152H is a CFTR mutation characterized by G-to-C base change at base number 3586 (exon 18), resulting in an aspartic acid to histidine substitution at position 1152 of the mature protein (9). Login to comment 21 ABCC7 p.Asp1152His D1152H is a class IV mutation associated with residual CFTR function (9) and has not been considered consistently as a CF-causing mutation (10, 11). Login to comment 23 ABCC7 p.Asp1152His The D1152H mutation has been identified in few symptomatic CF subjects (14-16), in male subjects with congenital bilateral absence of the vas deferens (CBAVD) (17, 18), and in limited numbers of subjects undergoing antenatal diagnosis or systematic neonatal screening (15, 19). Login to comment 24 ABCC7 p.Asp1152His Furthermore, D1152H was recently added to screening panels that are used for pre-marital and pre-natal carrier screening in selected populations (12). Login to comment 26 ABCC7 p.Asp1152His The D1152H mutation was first reported in a 57-year-old subject with mild pulmonary disease, pancreatic sufficiency and normal sweat chloride values (20). Login to comment 28 ABCC7 p.Asp1152His Mussaffi et al. studied nine CF subjects carrying the D1152H mutation and concluded that their phenotypes were widely variable: although some subjects showed no sign of disease, lung disease was evident from infancy in others and was severe in some adults (15). Login to comment 29 ABCC7 p.Asp1152His Thus, characterization of the clinical phenotype associated with D1152H mutation in the CFTR gene in large series of subjects appears important to provide guidance for pre-natal counseling and information for families of children diagnosed by neonatal screening. Login to comment 30 ABCC7 p.Asp1152His In the present study, we analyzed phenotypic manifestations in subjects carrying two CFTR mutations, including a D1152H allele, on separate chromosomes (i.e. in trans) using data from the French Cystic Fibrosis Registry, which represent more than 80% of the French CF population. Login to comment 32 ABCC7 p.Asp1152His Methods Identification of D1152H subjects The French Cystic Fibrosis Registry contains data from CF subjects collected by the CF care centers (n = 4744 subjects), representing more than 80% of the French CF population. Login to comment 34 ABCC7 p.Asp1152His The Registry was screened from 1999 to 2005 to identify subjects carrying the D1152H mutation in trans with another CF mutation. Login to comment 40 ABCC7 p.Asp1152His ABCC7 p.Asp1152His The p.D1152H mutation (abbreviated D1152H) is a CFTR mutation characterized by G-to-C base change at base number 3586 (exon 18, c.3454 according to the recommended international nomenclature with the A of the ATG start codon numbered as +1), resulting in an aspartic acid to histidine substitution at position 1152 of the mature protein (9). Login to comment 42 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr The CF genetic analysis panel used in France seeks for 32 mutations: G85E, 394delTT, 621+1G>T, 711+1G>T, R334W, R347P, R347H, 1078delT, 5T/7T/9T, A455E, F508del, I507del, V520F, 1717-1G>A, G542X, G551D, R553X, R560T, S549R (T>G), S549N, 1898+1G>A, 2183AA>G, 2184delA, 2789+5G>A, 3120+1G>A, R1162X, 3659delC, 3849+10kbC>T, W1282X, 3905insT, 3876delA, N1303K. Login to comment 43 ABCC7 p.Asp1152His The D1152H mutation is not included in this panel and is also not included in the panel used in the systematic neonatal screening performed in France since 2002 (CF30 Elucigen ARMS Kit). Login to comment 44 ABCC7 p.Asp1152His Thus, the D1152H mutation was identified in all patients by extensive CFTR mutation analysis after the finding of one common CFTR mutation and/or because of clinical suspicion of CF (10). Login to comment 55 ABCC7 p.Asp1152His In D1152H subjects, pancreatic status was further confirmed using fecal elastase measurements. Login to comment 61 ABCC7 p.Asp1152His Selection of the CF cohort subjects To compare the D1152H subjects with a group of CF cohort subjects, we selected subjects from the French Cystic Fibrosis Registry cohort as follows. Login to comment 65 ABCC7 p.Asp1152His We compared age at diagnosis, age at last evaluation, sweat chloride concentrations, pancreatic and nutritional status, and airway colonization by Pseudomonas aeruginosa between D1152H and PI and PS CF cohort subjects. Login to comment 66 ABCC7 p.Asp1152His Severity of pulmonary involvement was evaluated using FEV1 and FVC (percentage predicted); in these studies, data were available only in subjects over 6 years (n = 39 for D1152H subjects vs n = 2900 for CF subjects). Login to comment 68 ABCC7 p.Asp1152His Comparisons of data obtained in D1152H subjects and in PI and PS CF cohort subjects were performed using anova test followed by Tukey`s test for multiple comparisons (for normally distributed variables) or chi-squared tests (for categorical variables). Login to comment 71 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Results Genotypes and clinical characteristics at diagnosis in D1152H subjects We identified 42 subjects carrying at least one D1152H allele in trans with another CFTR mutation (41 compound heterozygotes and 1 homozygote) in a nationwide basis in France. Login to comment 77 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Sweat chloride concentrations and nasal PDs in D1152H and in CF cohort subjects Sweat chloride concentrations were available in 38 of 42 (90.5%) D1152H subjects and in 2300 of 3570 (64%) CF cohort subjects. Login to comment 78 ABCC7 p.Asp1152His Sweat chloride concentrations were lower in D1152H subjects than in PI and in PS CF subjects (p < 0.05; Fig. 1). Login to comment 79 ABCC7 p.Asp1152His Sweat chloride concentrations were normal (<40 mmol/l) in 13 of 38 (34.2%) D1152H subjects vs 10 of 1887 (0.5%) PI CF subjects and 25 of 413 (6.1%) PS CF subjects. Login to comment 80 ABCC7 p.Asp1152His Concentrations in the intermediate range (40-60 mmol/l) were found in 14 of 38 (36.8%) D1152H subjects vs 53 of 1887 (2.8%) PI CF subjects and 43 of 413 (10.4%) PS CF subjects. Login to comment 81 ABCC7 p.Asp1152His Elevated concentrations (>60 mmol/l) were found in 11 of 38 (29.0%) D1152H subjects vs 1824 of 1887 (96.7%) PI CF subjects and 345 of 413 (83.5%) PS CF subjects. Login to comment 82 ABCC7 p.Asp1152His D1152H subjects were less likely to have sweat chloride concentrations >60 mmol/l compared with PI CF subjects (p < 0.0001) and with PS CF subjects (p = 0.07; chi-squared test). Login to comment 83 ABCC7 p.Asp1152His Nasal PD measurements were performed in eight D1152H subjects in a single center (see Table 2). Login to comment 87 ABCC7 p.Asp1152His In subject #7, who had normal PD and normal Wilschanski`s index (0.3), the sweat test was also normal and it was the finding of the common 394delTT mutation that prompted the complete CFTR genotyping and the finding of the D1152H mutation. Login to comment 88 ABCC7 p.Asp1152His Classification of the D1152H subjects according to the consensus report on the diagnosis of CF (10) Based on the recent consensus report on the diagnosis of CF (10), 10 subjects could be classified as having classic CF (sweat chloride >60 mmol/l and clinical symptoms, Fig. 2). Login to comment 91 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Four of the F508del/D1152H asymptomatic subjects were diagnosed by systematic neonatal screening and were under 2-year old; the last asymptomatic F508del/D1152H (#33) was diagnosed by genetic counseling and was aged 16 years at last evaluation. Login to comment 92 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His Characteristics of the D1152H homozygous subject The only D1152H/D1152H subject was diagnosed with male infertility related to CBAVD at the age of 34 years. Login to comment 97 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Comparison of clinical characteristics in D1152H and in CF cohort subjects Age at diagnosis and at last evaluation In D1152H subjects, not diagnosed by neonatal screening (n = 38), median age at diagnosis Table 1. Login to comment 98 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Ser549Asn ABCC7 p.Arg1070Gln ABCC7 p.Gln552* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Glu116Lys ABCC7 p.Ser1206* Diagnostic features in 42 D1152H subjects according to the other CFTR mutation class Subject Sex (M/F) Other CFTR mutation Sweat Cl- mean (mmol/l) Age at diagnosis (years) Presentation at diagnosis Class I mutations 1 F W1282X 58 4 Pneumonia recurrent bronchitis 2 F W1282X 25 74 Bronchiectasis 3 M W1282X 43 33 CBAVD 4 M G542X 48 39 CBAVD 5 M G542X 72 27 CBAVD 6 F S1206X 18 13 Recurrent bronchitis+ diarrhea 7 F 394delTT 19 41 Bronchiectasis 8 F 394delTT 25 18 Bronchiectasis 9 F Q552X 56 43 Bronchiectasis Class II mutations 10 F F508del 13 42 Bronchiectasis 11 F F508del 40 32 Bronchiectasis 12 F F508del 52 23 Bronchiectasis 13 M F508del 51 15 Bronchiectasis 14 F F508del 100 24 Bronchiectasis 15 M F508del 79 26 Bronchiectasis 16 F F508del - 43 Bronchiectasis 17 M F508del - 23 Bronchiectasis 18 F F508del 19 55 Bronchiectasis 19 F F508del 25 33 Bronchiectasis 20 F F508del 78 15 Bronchiectasis 21 M F508del 90 40 Bronchiectasis 22 F F508del 44 42 Bronchiectasis 23 M F508del 88 11 Bronchiectasis 24 F F508del 63 47 Bronchiectasis 25 F F508del 43 33 Bronchiectasis 26 M F508 del 62 49 Bronchiectasis 27 M F508del 20 - CBAVD 28 M F508del - 27 CBAVD 29 M F508del 42 36 CBAVD 30 M F508del 36 34 CBAVD 31 M F508del 40 36 CBAVD 32 M F508del 41 30 CBAVD 33 M F508del 82 9 Asymptomatic genetic counseling 34 M F508del - 0 Neonatal screening 35 F F508del 53 0 Neonatal screening 36 F F508del 35 0 Neonatal screening 37 M F508del 35 0 Neonatal screening Class III mutation 38 F S549N 75 31 Bronchiectasis Class IV mutations 39 M E116K 80 41 ABPA+ diarrhea 40 M D1152H 34 34 CBAVD 41 M R1070Q 56 38 CBAVD Class V mutation 42 M 3849+10kbC>T 31 40 Asymptomatic genetic counseling ABPA, allergic bronchopulmonary aspergillosis; CBAVD, congenital bilateral absence of the vas deferens. Login to comment 100 ABCC7 p.Asp1152His When compared to PI (n = 3041) and PS (n = 529) CF subjects not diagnosed by neonatal screening in the Registry, age at diagnosis and age at last evaluation were markedly higher in D1152H subjects (p < 0.05; see Fig. 3). Login to comment 101 ABCC7 p.Asp1152His None of the D1152H subjects identified in this study (n = 42) had died or required lung transplantation at the time of writing. Login to comment 102 ABCC7 p.Asp1152His Respiratory manifestations Respiratory symptoms were present in 34 of the 42 (80.9%) D1152H subjects; among them, 28 (66.7%) had bronchiectasis (as demonstrated by D1152HCF cohort 0 50 100 150 Sweat chloride concentrations (mmol/l) PI PS P<0.05 P<0.05 P<0.05 Fig. 1. Login to comment 103 ABCC7 p.Asp1152His Sweat chloride concentrations in CF cohort and in D1152H subjects. Login to comment 104 ABCC7 p.Asp1152His Sweat chloride concentrations were compared using available data obtained in pancreatic insufficient (PI, n = 1887) and in pancreatic sufficient (PS, n = 413) CF cohort subjects and in D1152H subjects (n = 38). Login to comment 107 ABCC7 p.Asp1152His Bronchial colonization with at least one pathogen characteristic of CF (H. influenzae, P. aeruginosa, Staphylococcus aureus, and S. maltophilia) was present in 29 of the 42 (69.0%) D1152H subjects. Login to comment 108 ABCC7 p.Asp1152His Pulmonary function tests were available in all D1152H subjects except in three young children. Login to comment 110 ABCC7 p.Asp1152His Estimated annual rates of decline in FEV1 and in FVC were considerably lower in D1152H compared with PI CF cohort subjects. Login to comment 111 ABCC7 p.Asp1152His Decline in lung function in D1152H subjects was not significantly different from PS CF cohort subjects (Table 3 and Fig. 4). Login to comment 112 ABCC7 p.Asp1152His Colonization with P. aeruginosa was present in only 11 of the 42 (26.2%) D1152H subjects, a rate that was lower than in PI CF cohort subjects, but was comparable with findings in PS CF subjects (see Table 3). Login to comment 113 ABCC7 p.Asp1152His Within the D1152H group, subjects colonized with P. aeruginosa (n = 11) had a higher estimated annual rate of decline in FEV1 and in FVC compared to those non-colonized with P. aeruginosa (n = 28): 1.00 ± 0.59% vs 0.45 ± 0.72% (p = 0.03) and 0.65 ± 0.42% vs 0.34 ± 0.59% (p = 0.13), respectively. Login to comment 114 ABCC7 p.Asp1152His Nutritional and pancreatic status In adults (age > 16 years), median BMI was higher in D1152H adult subjects (n = 37) compared with adult PI and PS CF cohort subjects (p < 0.05, Table 3). Login to comment 115 ABCC7 p.Asp1152His ABCC7 p.Asp1152His None of the D1152H adult subjects had a BMI < 18 kg/m2 and the five D1152H children had normal nutritional status (IBW > 90% predicted, not shown). Login to comment 116 ABCC7 p.Asp1152His Pancreatic insufficiency was diagnosed in 12 of the 42 (28.6%) D1152H subjects (11 adults and 1 child, all with a second class I or class II mutation), and was significantly less prevalent than in CF cohort subjects (p < 0.001, Table 3). Login to comment 120 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Asp1152His ABCC7 p.Ser1206* Nasal epithelial physiologic properties in eight CF subjects carrying the D1152H mutation Nasal bioelectric properties Subject Other CFTR mutation Sweat Cl- mean (mmol/l) Maximal PD (mV) Amil (mV) Cl-/amil (mV) Iso/Cl- (mV) Wilchanski`s indexa Class I mutations 2 W1282X 25 -44 38 -2 -14 0.7 3 W1282X 43 -34 9 -1 1 1.0 4 G542X 48 -16 12 -3 -1 0.7 6 S1206X 18 -44 28 -11 0 0.7 7 394delTT 19 -25 25 -15 -15 0.3 8 394delTT 25 -42 23 -4 -4 0.7 Class II mutation 18 F508del 19 -19 9 0 0 1.0 Class V mutation 42 3849+10 kb C>T 31 -19 9 1 3 1.6 Cl- , chloride; PD, potential difference; Amil, amiloride; Iso, isoproterenol. Login to comment 122 ABCC7 p.Asp1152His D1152H subjects n=42 sweat chloride concentrations Clinical symptoms* Yes No n=13 n=1 Asymptomatic at age 16 yr. F508del 40-59 mmol/l n=14 Yes No n=10 n=1 ≤39 mmol/l n=13 unknown n=4 ≤60 mmol/l n=11 Yes No n=10 n=3 Nonclassic CF asymptomatic at age 1 yr. F508del asymptomatic at age • 1yr (n=1). Login to comment 126 ABCC7 p.Asp1152His Clinical features in 42 D1152H subjects according to sweat chloride concentrations and symptoms. Login to comment 129 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Comparison of clinical characteristics between CF cohort and D1152H subjects CF cohort (n = 3570) Variables PI (n = 3041) PS (n = 529) D1152H (n = 42) Male, n (%) 1620 (53) 273 (52) 22 (52) FEV1, percentage predicteda 70 (45; 91) 82 (57; 99)c 89 (56; 100)c Estimated annual loss in FEV1, percentage predicted 1.56 (0.54; 2.56) 0.78 (0.09; 1.61)c 0.37 (0.00; 0.89)c FVC, percentage predicteda 83 (64; 98) 90 (74; 102)c 92 (72; 105) Estimated annual loss in FVC, percentage predicted 0.86 (0.12; 1.74) 0.42 (-0.13; 1.12) 0.24 (-0.16; 0.77) Pseudomonas aeruginosa colonization, n (%)b 1586 (54.8) 137 (30.0)c 11 (26.2)c BMI, kg/m2 Median (IQR) 19.4 (17.9; 21.1) 20.9 (19.3; 22.7)c 21.9 (20.7; 24.9)c,d BMI ≥ 20, n (%) 650 (39.9) 198 (64.3)c 30 (81.1)c,d BMI < 20, n (%) 981 (60.1) 110 (35.7)c 7 (18.9)c,d All data are shown as median (IQR) or numbers of patients (%) in each group. Login to comment 132 ABCC7 p.Asp1152His a Based on available data in D1152H subjects (n = 39), PI CF subjects (n = 2483) and PS CF subjects (n = 442) over 6 years. Login to comment 133 ABCC7 p.Asp1152His bBased on available data in D1152H subjects (n = 39), PI CF subjects (n = 2897) and PS CF subjects (n = 457). Login to comment 136 ABCC7 p.Asp1152His with a D1152H CFTR mutation in trans with another CFTR mutation. Login to comment 139 ABCC7 p.Asp1152His Comparison of age at diagnosis (left) and age at last evaluation (right) between cystic fibrosis (CF) cohort subjects and D1152H subjects. Login to comment 140 ABCC7 p.Asp1152His Age at diagnosis and age at last evaluation were compared in subjects not diagnosed by systematic neonatal screening in pancreatic insufficient (n = 3041) and pancreatic sufficient (n = 529) CF cohort subjects vs D1152H subjects (n = 38). Login to comment 142 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Estimated annual decline (% predicted) 0 1.5 3 4.5 -0.5 P<0.05 D1152H FEV1 CF cohort PI PS NS P<0.05 D1152H FVC CF cohort PI PS NS NS P<0.05 FEV1 PI PS FVC PI PS FEV1FEV1 FVCFVC Fig. 4. Login to comment 143 ABCC7 p.Asp1152His Estimated annual decline in forced expiratory volume in 1 s (FEV1) and in forced vital capacity (FVC) in cystic fibrosis (CF) cohort and in D1152H subjects. Login to comment 144 ABCC7 p.Asp1152His Estimated annual decline in FEV1 and FVC were calculated as described in Methods (27), using available data obtained in pancreatic insufficient (PI, n = 2483) and in pancreatic sufficient (PS, n = 442) CF cohort subjects and in D1152H subjects (n = 39). Login to comment 147 ABCC7 p.Asp1152His However, the estimated annual rate of decline in FEV1 was extremely low in D1152H subjects and two-third of these subjects had an FEV1 > 80% at the time of last evaluation. Login to comment 149 ABCC7 p.Asp1152His Asymptomatic subjects were infrequent in subjects carrying D1152H with a severe CFTR mutation and were found exclusively among neonates and children. Login to comment 150 ABCC7 p.Asp1152His We conclude that D1152H is a mutation that when present in trans with a CF-causing mutation, can cause a variable phenotype, ranging from normal to CF, usually characterized by mild pulmonary disease and pancreatic sufficiency. Login to comment 152 ABCC7 p.Asp1152His However, it is likely that all subjects carrying the D1152H mutation in trans with another CFTR mutation in France were not identified. Login to comment 153 ABCC7 p.Asp1152His First, subjects with milder forms of the disease (e.g. CFTR-related disease) are less likely to be diagnosed based on clinical symptoms, suggesting that our cohort represents the most severe aspects of D1152H-associated disease. Login to comment 154 ABCC7 p.Asp1152His Next, in the 2005 French Cystic Fibrosis Registry, 11.7% of the subjects has at least one unidentified CFTR mutation; it is conceivable that D1152H mutation was not identified in some of these subjects. Login to comment 155 ABCC7 p.Asp1152His ABCC7 p.Asp1152His However, due to the low frequency of the D1152H mutation in France, the possible number (if any) of undiagnosed D1152H mutation among CF subjects with unidentified mutation is probably very low and is unlikely to alter our conclusions. Login to comment 156 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Our data confirm and extend the report by Mussaffi et al. who studied nine D1152H subjects and suggested that subjects carrying the D1152H mutation in trans with another CFTR mutation may show a wide range of disease severities (15). Login to comment 157 ABCC7 p.Asp1152His Part of the phenotypic variability found in D1152H subjects may be related to the other CFTR mutations, which determine the residual level of CFTR function. Login to comment 158 ABCC7 p.Asp1152His Variable phenotypes were also found in subjects with the same CFTR genotype (e.g. F508del/D1152H). Login to comment 160 ABCC7 p.Asp1152His The design of this Registry study did not allow for extensive characterization of disease modifying variants in D1152H subjects. Login to comment 161 ABCC7 p.Asp1152His Clearly, additional studies will be required to fully understand mechanisms of phenotypic variability in D1152H subjects. Login to comment 162 ABCC7 p.Asp1152His The clinical significance of the D1152H mutation in trans with another CFTR mutation has been matter of debate because only limited numbers of subjects with this genotype have been studied (14, 15). Login to comment 163 ABCC7 p.Asp1152His Thus, in a recent consensus report on the diagnosis of CF, D1152H was not included in the list of CF-causing mutations (10). Login to comment 164 ABCC7 p.Asp1152His ABCC7 p.Asp1152His In another recent consensus report, it was suggested that D1152H/F508del subjects may show a clinical spectrum ranging from CBAVD to CF; these authors suggested that D1152H was a 'borderline` mutation that could be classified either as CF-causing or CFTR-related disorders associated mutation (11). Login to comment 165 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His Our results combined with previous literature indicate that (i) D1152H causes a change in amino sequence that affects CFTR function in vitro (9), (ii) D1152H is detected in a set number of unrelated individuals with CF as shown in our study, (iii) frequency in the general population is probably low: we found only one D1152H homozygous subject in France. Login to comment 166 ABCC7 p.Asp1152His Furthermore, in an analysis of 116 healthy subjects in a single genetic laboratory, we found no D1152H mutation (frequency 0 of the 232 alleles; personal communication, Dr Bienvenu). Login to comment 167 ABCC7 p.Asp1152His (iv) Asymptomatic D1152H/F508del subjects were infrequent and always found in neonates or children in whom clinical manifestations may occur later due to the age-related progression of the disease. Login to comment 168 ABCC7 p.Asp1152His Although our findings may need to be replicated in another cohort, these results strongly support the recent statement (11) that D1152H should be added to the list of CF-causing mutations and CFTR-related associated mutations. Login to comment 169 ABCC7 p.Asp1152His Prolonged survival has been previously reported in subjects carrying the D1152H mutation as well as in subjects carrying class IV or class V CFTR mutations (5, 30). Login to comment 171 ABCC7 p.Asp1152His However, it is noteworthy that none of the D1152H subjects identified since 1999 had died or required lung transplantation. Login to comment 172 ABCC7 p.Asp1152His More than 50% of D1152H subjects were >40 years at last evaluation. Login to comment 173 ABCC7 p.Asp1152His Taken together, these results indicate that D1152H allele is associated with one of the most prolonged survival in CF subjects, as previously suggested in case reports (14, 20, 25, 31) and in a small series of cases (15). Login to comment 174 ABCC7 p.Asp1152His ABCC7 p.Asp1152His In summary, we report on the first large series of subjects with a D1152H in trans with another CFTR mutation and we suggest that D1152H is a disease causing mutation. Login to comment 176 ABCC7 p.Asp1152His Although individual outcomes remain unpredictable, these data provide important information that may be of particular interest to subjects and to parents of children who receive a diagnosis of D1152H-associated CF. Login to comment