ABCMdb

PMID: 22156145

Peleg L, Karpati M, Bronstein S, Berkenstadt M, Frydman M, Yonath H, Pras E
The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis.
J Med Screen. 2011;18(4):169-72. Epub 2011 Dec 7., [PubMed]

Sentences

No. Mutations Sentence Comment

137 ABCC7 p.Asp1152His Objective To assess the frequency of the D1152H mutation in the CFTR gene in normal individuals, in cystic fibrosis (CF) patients and in the setting of prenatal diagnosis. Login to comment 139 ABCC7 p.Asp1152His Methods We retrospectively analyzed the frequency of D1152H in a large cohort of healthy individuals who were screened as part of a routine prenatal care programme, in individuals referred due to CF-related symptoms and in the setting of prenatal diagnosis. Login to comment 140 ABCC7 p.Asp1152His Results We found one asymptomatic homozygous female and 195 D1152H carriers among 49,940 healthy individuals screened, establishing a carrier rate of 1:255 for this mutation. Login to comment 141 ABCC7 p.Asp1152His We detected D1152H in nine of 103 individuals referred due to CF-related symptoms. Login to comment 143 ABCC7 p.Asp1152His During this period D1152H was detected in three pregnancies, two of which were aborted. Login to comment 144 ABCC7 p.Asp1152His Conclusion The increased frequency of D1152H in individuals referred due to CF-related symptoms compared with healthy individuals included in the CF carrier screening programme (P , 0.001) clearly indicates that it is a disease-causing mutation. Login to comment 148 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His The D1152H mutation is associated with residual CFTR function and abnormal chloride gating.10 Initially this mutation in its homozygous form or in conjunction with another CFTR mutation was associated mainly with CBAVD and mild, late onset pulmonary disease; with borderline or normal sweat chloride values.7,11 Moreover, among Hispanics D1152H was found in 6% of the referrals for routine screening but in no Hispanic CF patients, questioning whether D1152H is no more then a functional polymorphism;12 and in a recent consensus report D1152H was not categorized as a disease-causing mutation.13 We have included D1152H in our CF carrier screening programme and in patient screening since 2001. Login to comment 149 ABCC7 p.Asp1152His During these years we have detected D1152H in healthy individuals who took part in our screening programme, in patients, and in three fetuses studied prenatally. Login to comment 157 ABCC7 p.Asp1152His ABCC7 p.Asp1152His One hundred and ninety-five individuals were found heterozygous for the D1152H mutation and one 30-year-old female without any CF-related symptoms was found homozygous for D1152H. Login to comment 162 ABCC7 p.Asp1152His Of the 37 patients with two mutations, D1152H was found in nine (Table 3), comprising 16.9% of the mutations detected among suspected patients. Login to comment 163 ABCC7 p.Asp1152His Four were homozygous for D1152H, and five were compound heterozygotes. Login to comment 164 ABCC7 p.Asp1152His Two of the D1152H homozygotes were referred because of CBAVD and two due to respiratory symptoms. Login to comment 166 ABCC7 p.Asp1152His D1152H was not detected in any of the nine patients with a single mutation. Login to comment 167 ABCC7 p.Asp1152His Between 2001 and 2010 we detected three D1152H compound heterozygote fetuses (Table 4). Login to comment 173 ABCC7 p.Trp1282* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His Carrier rate Total individuals screened 49,940 Total CF carriers 1524 1:33 D1152H carriers 195 1:255 Table 3 D1152H in conjunction with CF-related symptoms No. Mutations Age Sex Reason for referral 1 D1152H/ W1282X 30 F Mild asthma during childhood that disappeared in adulthood. Login to comment 174 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His No pancreatic insufficiency. 2 D1152H/ F508del 36 M CBAVD, no respiratory symptoms or pancreatic insufficiency. 3 D1152H/ F508del 40 M CBAVD no respiratory symptoms or pancreatic insufficiency. 4 D1152H/ D1152H 31 M CBAVD no respiratory symptoms or pancreatic insufficiency. 5 D1152H/ D1152H 8 M Recurrent pneumonias since infancy. Login to comment 176 ABCC7 p.Trp1282* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His No pancreatic insufficiency. 6 D1152H/ D1152H 40 M CBAVD, no respiratory symptoms or pancreatic insufficiency. 7 D1152H/ W1282X 30 F Recurrent pneumonia during childhood. Login to comment 178 ABCC7 p.Trp1282* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His No pancreatic insufficiency. 8 D1152H/ W1282X 21 M CBAVD, no respiratory symptoms or pancreatic insufficiency. 9 D1152H/ D1152H 17 M Bronchiectasis, recurrent lung infections, lately with Aspergillus, nasal polyps, no pancreatic insufficiency. Login to comment 180 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly85Glu ABCC7 p.Ser549Ile ABCC7 p.Tyr1092* ABCC7 p.Asp1152His ABCC7 p.Ile1234Val ABCC7 p.Ile1234Val ABCC7 p.Trp1089* ABCC7 p.Arg75* ABCC7 p.Thr360Lys ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys ABCC7 p.Gln359Lys of mutations Group of mutations 2001 Ashkenazi Jews 7 Group A Non-Ashkenazi Jews 11 Group A þ B Georgian Jews 12 Group A þ B þ T360K/Q359K 9.2004-7.2005 Yemenite Jews 12 Groups A þ B þ I1234V Iraqi Jews 12 Groups A þ B þY1092X 8.2005-12.2007 Iraqi Jews 14 Groups A þ B þY1092X þ 3121-1G-A 1.2008-2010 14 mutations for all 14 Groups A þ B þ C Georgian Jews 15 Groups A þ B þ C þ T360K/Q359K Arabic population 19 Groups A þ B þ C þ D Group A: G542X, W1282X, N1303K, F508del, 3849 þ 10KbC-T, 1717-1G-A, D1152H Group B: W1089X, G85E, 405 þ 1G-A, S549R(T-G) Group C: Y1092X, 3121-1G-A, I1234V Group D: 4010delTATT, S549I, 3120 þ 1Kbdel18.6Kb, 2183AA-G, R75X Between 2005-2008 the Iraqi population was screened for an additional mutation 2751 þ 1insT. Login to comment 181 ABCC7 p.Asp1152His In 2009 the Israeli Society of Medical Genetics recommended excluding this mutation from the screening programmes due to its low prevalence DISCUSSION In this report we present our experience with the D1152H mutation in a low-risk healthy population screened for CF carrier state, in symptomatic referrals and in prenatal diagnosis. Over representation of a mutation in patients, compared with the general population is considered one of the cornerstones in differentiating a mutation from a benign polymorphism. Login to comment 182 ABCC7 p.Asp1152His We found a much higher frequency of the D1152H allele in individuals referred due to possible CF (13 of 206 alleles) compared with individuals who took part in the screening programme (195 of 99,880; P , 0.0001). Login to comment 183 ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His These results stand in sharp contrast to those of Sugerman et al., who found D1152H in 6% of the Hispanic population but not in Hispanic CF patients.12 A carrier rate of 1:255 for D1152H combined with a general carrier rate of 1:33 implies that roughly 1:33,000 individuals is a compound heterozygote or homozygote for D1152H, afigure in line with the single asymptomatic homozygote that we have detected in our screening programme. Login to comment 184 ABCC7 p.Asp1152His ABCC7 p.Asp1152His In this study, the overwhelming representation of D1152H compound heterozygotes and homozygotes in the patient cohort (9 of 103) serves as additional evidence that D1152H is associated with clinical symptoms thus supporting two recent publications. Login to comment 185 ABCC7 p.Asp1152His ABCC7 p.Asp1152His In 2006 Mussaffi et al. described nine patients, two homozygous for D1152H and seven compound heterozygotes, aged eight months to 54 years with variable CF manifestations which included lung and pancreatic involvement, and CBAVD.14 Although the symptoms were often mild, the authors concluded that D1152H-associated lung disease can appear in early infancy and in adults diagnosed at a late age can be quite severe. Login to comment 186 ABCC7 p.Asp1152His Burgel et al. described 42 patients with the D1152H mutation; 80% presented with respiratory symptoms and 25% with CBAVD.15 Clinical manifestations among patients presented in our study are similar to those reported in the two previous series. Login to comment 187 ABCC7 p.Asp1152His Four of our patients presented with respiratorysymptoms and although onewas diagnosed at the age of eight months, all of the others were diagnosed at an older age, indicating that D1152H is associated with a relatively mild disease. Login to comment 189 ABCC7 p.Asp1152His Mussaffi et al. found that two of the three adult males in their study had children, suggesting that homozygosity or compound heterozygosity for D1152H in males does not invariably result in infertility. Login to comment 191 ABCC7 p.Asp1152His The atypical disease and relatively mild symptoms pose an ever increasing counselling problem when faced with a fetus homozygous or compound heterozygous for D1152H as exemplified by the three cases described above. Login to comment 196 ABCC7 p.Asp1152His In contrast to the decision made by these parents, Mussaffi et al. described a fetus with dilated bowel loops and the D1152H/F508del genotype, where the parents elected to continue the pregnancy.14 Normal meconium was passed 16 hours after birth and subsequent studies did not reveal pancreatic insufficiency, although long-term follow-up revealed mild pulmonary symptoms and hyperinflation on a chest X-ray. Login to comment