ABCMdb

PMID: 17594398

Narzi L, Ferraguti G, Stamato A, Narzi F, Valentini SB, Lelli A, Delaroche I, Lucarelli M, Strom R, Quattrucci S
Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up.
Clin Genet. 2007 Jul;72(1):39-46., [PubMed]

Sentences

No. Mutations Sentence Comment

43 ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys Five of the 31 mutations included in the basic genetic panel were found to occur in more than 1 of the 64 alleles examined (Table 1 and Fig. 1): F508del in 15 alleles (23.4%), N1303K in four alleles (6.3%), 2789 1 5G-.A in two alleles (3.1%), R117H in two alleles (3.1%), and R347P in two alleles (3.1%). Login to comment 46 ABCC7 p.Leu997Phe The L997F and the P5L mutations were found, respectively, in five (7.8%) and four (6.3%) alleles, which is a significantly higher frequency than that found in the general population (see Discussion) (w2 ¼ 10.6, d.f. ¼ 1, p , 0.01 and w2 ¼ 11.7, d.f. ¼ 1, p , 0.01, respectively). Login to comment 48 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Ser1235Arg ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Arg1162Leu ABCC7 p.Pro1013Leu ABCC7 p.Asp836Tyr ABCC7 p.Asp806Gly CFTR genotypes, IRT2 and sweat test values of the 32 newborns analyzed Newborn CFTR genotype IRT2 Sweat test (mmol/l [Cl2 ]) at enrolment True heterozygous subjects 1 N1303K/1 Negative 18 2 2183AAtoG/1 Negative 11 3 G85E/1 Positive 19 4 F508del/1 Negative 21 5 F508del/1 Negative 20 6 R117H/1 Negative 6 7 1717-1GtoA/1 Positive 7 8 W1282X/1 Negative 14 9 278915GtoA/1 Negative 23 10 N1303K/1 Negative 19 11 F508del/1 Negative 14 12 G542X/1 Negative 39 % of positivity ¼ 16.7% Average Æ SD ¼ 18 Æ 9 Compound heterozygous subjects 13 F508del/D806G Positive 24 14 F508del/D836Y Negative 12 15 R347P/R1162L Negative 18 16 F508del/P5L (TG)11T5 Negative 16 17 F508del/L997F Positive 32 18 R347P/D1152H Positive 42 19 F508del/P5L Negative 42 20 278915GtoA/71113AtoG Positive 33 21 F508del/P5L Positive 39 22 F508del (TG)12T7/(TG)12T5 Negative 23 23 N1303K/S1235R (TG)12T7 Negative 30 24 F508del/L997F Positive 34 25 F508del/(TG)12T5 Negative 34 26 R117H/(TG)12T7 Positive 22 27 F508del/P1013L Positive 8 28 F508del/L997F Negative 28 29 N1303K/(TG)12T5 Positive 13 30 F508del/L997F Positive 50 31 R1162X/P5L Negative 31 32 L997F/S549R(AtoC) Positive 38 % of positivity ¼ 55.0% Average Æ SD ¼ 29 Æ 12 CFTR, cystic fibrosis transmembrane conductance regulator. Login to comment 56 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Arg1162Leu ABCC7 p.Pro1013Leu ABCC7 p.Asp836Tyr ABCC7 p.Asp806Gly This type of analysis has already been performed for some of the uncommon mutations found in this work (R1162L, S1235R and L997F, see Discussion), while we performed frequency studies for D836Y, P1013L, P5L and D806G. Login to comment 58 ABCC7 p.Leu997Phe We also assessed the frequency of L997F in our general population, finding one allele with this mutation, which is similar in frequency (0.5%) to that found in a previous study (see Discussion). Login to comment 59 ABCC7 p.Ser1235Arg In addition, an extended genetic analysis did not detect any other mutations in the alleles carrying the seven mutations listed above (with the exception of S1235R, which was found in a complex allele with the (TG)12T7 variant tract). Login to comment 75 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Asp1152His Discussion The majority of the mutations found (F508del, R347P, D1152H, 2789 1 5G-.A, 711 1 3A-.G, N1303K, R117H, R1162X, S549R(A-.C), 2183AA-.G, G85E, 1717-1G-.A, G542X, and W1282X) have an established pathogenic role (26-44). Login to comment 77 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Arg1162Leu ABCC7 p.Pro1013Leu ABCC7 p.Asp836Tyr ABCC7 p.Asp806Gly By contrast, the pathogenic role of some of the uncommon mutations found (P5L, D836Y, P1013L, D806G, L997F, S1235R, and R1162L) is still a matter of debate (15, 17, 28, 32, 48-58). Login to comment 78 ABCC7 p.Pro1013Leu ABCC7 p.Asp836Tyr ABCC7 p.Asp806Gly The P5L, D836Y, P1013L, and D806G mutations were found to be absent from the general population in the search performed in this work. Login to comment 79 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe L997F, S1235R and Table2.Clinicalfeaturesoftheninenewbornsfollowedupfor4years NewbornGenotype First sweattest (atbirth) Average sweattest (1-4years) Symptomsat screening Symptomsduring 4-yearfollow-upChestX-ray Chrispin score Weight (centiles) Height (centiles) Abdominal ultrasonography Bacterial isolates 28F508del/L997F2843NegativeChronicrhinosinusitis andpharyngitis; sinusdisease Positive610094Positive(initialfocal biliarycirrhosis) Negativeculture 24F508del/L997F3469NegativeHospitalizationfor severebronchiolitis; recurrentrhino- pharyngitis,sometimes productivecough Positive63243Positive (hepatomegaly) Negativeculture 30F508del/L997F5062NegativePharyngitis,recurrent abdominalpain Positive42079Positive (thickeningof portalspaces) Negativeculture 27F508del/P1013L820NegativeNegativeNegative29976Positive (hepatomegaly) Negativeculture 31R1162X/P5L3171NegativeProductivecough, widespread osteoporosis, nasalobstruction Positive (bronchiectasis) 71898Positive (initialfocal biliarycirrhosis) Staphylococcus aureus 23N1303K/ S1235R(TG)12T7 3018NegativeSometimesrhinitisNegative26496NDNegativeculture 29N1303K/(TG)12T51328NegativeBronchiolitis,chronic rhinitis,sporadic episodesofcough Positive45921NDNegativeculture 32L997F/S549R(A-.C)3841NegativeEpisodicallyproductive cough,chronicrhinitis, bronchitis Positive75667NDNegativeculture 18R347P/D1152H4244NegativeNegativePositive104456NDS.aureus AverageÆSD¼30Æ1344Æ205Æ355Æ3070Æ26 ND,notdetermined. Login to comment 80 ABCC7 p.Arg1162Leu R1162L have also been shown, in previous reports (49, 54), to be less frequent in the general population (0.5%, a percentage confirmed in this work, 0.3% and 0.3%, respectively). Login to comment 81 ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Arg1162Leu The absence or lower frequency of L997F, S1235R and R1162L in the general population than in our target group is compatible with a possible pathogenic role of these mutations. Login to comment 82 ABCC7 p.Leu997Phe The L997F and P5L mutations were significantly more frequent in the newborns we studied than in the general population (7.8% and 6.3%, respectively). Login to comment 83 ABCC7 p.Ser1235Arg In all our subjects, each of these seven mutations was found as a unique mutation of the allele studied, with the exception of S1235R, for which a cis-acting effect by the (TG)12T7 variant tract found on the same allele may be hypothesized. Login to comment 96 ABCC7 p.Leu997Phe The high frequency of both L997F and P5L mutation suggests that these should be included in mutational panels that are specific for neonatal screening, at least in Italy. Login to comment