ABCMdb

PMID: 16189704

McGinniss MJ, Chen C, Redman JB, Buller A, Quan F, Peng M, Giusti R, Hantash FM, Huang D, Sun W, Strom CM
Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.
Hum Genet. 2005 Dec;118(3-4):331-8. Epub 2005 Sep 28., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Cys491Ser ABCC7 p.Ser158Thr ABCC7 p.Phe1099Leu ABCC7 p.Lys481Glu ABCC7 p.Thr1036Asn ABCC7 p.His949Leu ABCC7 p.Gly451Val We ascertained ten novel sequence variants that are potentially disease-associated: two deletions (c.1641AG>T, c.2949_2853delTACTC), seven missense mutations (p.S158T, p.G451V, p.K481E, p.C491S, p.H949L, p.T1036N, p.F1099L), and one complex allele ([p.356_A357del; p.358I]). Login to comment 52 ABCC7 p.Thr1036Asn ABCC7 p.Gly451Val Novel variant CFTR alleles were ascertained in three patients, including c.1641 AG>T, p.G451V, and p.T1036N; these are described below in detail. Login to comment 53 ABCC7 p.Arg1158* ABCC7 p.Ala1006Glu ABCC7 p.Val562Ile Finally, one CF patient with mild symptoms carried a complex allele [p.V562I; p.A1006E] and a nonsense mutation (p.R1158X) on the other allele. Login to comment 57 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala Subject 1 had a complex allele ([p.G576A; p.R668C]) which had been previously described in a patient with disseminated bronchiectasis (Pignatti et al. 1995). Login to comment 67 ABCC7 p.Phe1099Leu Two novel and apparently disease-associated sequence variants were identified and are discussed below in detail (c.2949_2953 delTACTC and p.F1099L). Login to comment 68 ABCC7 p.Pro750Leu ABCC7 p.Arg352Trp One patient carried an apparently novel complex CFTR allele ([p.R352W; p. P750L]). Login to comment 72 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Arg170His ABCC7 p.Arg1070Trp ABCC7 p.Ser912Leu ABCC7 p.Leu732* The two deletions Table 2 Atypical CF or nonclassic patients in whom extensive sequencing revealed two CFTR mutations Patient Genotype Phenotype Sex Age (years) Sweat chloride concentration (mmol/l) 1 p.S912L/DF508 Chronic lung and sinus disease F 52 Not done 2 p.R1070W/p.N1303K Recurrent respiratory infections F 4.5 2X intermediate 3 p.G551D/c.2789+2 InsA Pancreatic insufficiency, little lung involvement F 50 92, 96 4 c.3849+10kb C>T/p.L732X Failure to thrive, chronic cough, chronic sinusitis M 5.5 70,73 5 p.W1282X/p.R170H Chronic pancreatitis, CBVAD M 44 Borderline (c.1641 AG>T, and c.2949-2953 del TACTC) are expected to be severe disease-associated mutations, since they change the CFTR reading frame; the two patients harboring these novel deletions had a diagnosis of CF with elevated sweat chloride levels and carried a second, previously described, CF mutation. Login to comment 73 ABCC7 p.Ser945Leu ABCC7 p.His609Arg ABCC7 p.Val358Ile The patient with the Table 3 Classic CF patients in whom extensive sequencing revealed two CFTR mutations Phenotype Age (years) Sweat chloride concentration (mmol/l) Genotype after sequencing CF; meconium ileus at birth; respiratory symptoms 12 110,115 p.V358I/c.1198del6 CF; pulmonary symptoms; partial PI 30 Pos c.2307insA/p.S945L Classic CF; pancreatic and pulmonary symptoms 22 >100 p.H609R/c.1641AG>Ta Classic CF 10 ? Login to comment 74 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Leu206Trp ABCC7 p.Arg1158* ABCC7 p.Arg1066Cys ABCC7 p.Arg117Cys ABCC7 p.Tyr275* ABCC7 p.Arg75* ABCC7 p.Val562Ile ABCC7 p.Arg785* ABCC7 p.Thr1036Asn DF508/c.546insCTA CF; lung symptoms; PS; 2 sibs with CF NG Pos p.R1066C/c.3272-26 A>G Mild CF 40 115 [p.V562I;p.A1006E]b /p.R1158X CF, FTT 6 Not done DF508/c.1716G>A Classic CF 21 Not done p.R785X/c.2732insA Classic CF, PI 4 Not done DF508/p.R117C Classic CF 2 Not done DF508/p.R75X CF 19 Pos DF508/p.G451Va Mild CF 23 Pos DF508/p.L206W Classic CF 9 150s DF508/p.G542Xc Classic CF 15 Pos p.T1036N/p.T1036Na CF, PS 9 Pos DF508/c.3272-26 A>G Classic CF 33 Not done DF508/p.R117Hc Classic CF 35 Not done DF508/p.A455Ec CF 3 Pos p.G551D/p.Y275X a Novel CFTR variant b Complex CFTR allele c Both mutations are on the ACMG/ACOG panel Table 5 Diagnosis of CF in infants/newborns with abnormal newborn screening results Patient number Genotype Age at sequencing Sex Newborn screen result Sweat chloride concentration (mmol/l)a Phenotype 1 DF508/c.2789+2insA 3 months F Positive sweat test 88,96,89,84 Dx of CF, being treated prophylactically 2 DF508/c.2949del5b 3 months F IRT positive 105 Dx of CF 3 p.G551D/c.1259insA 14 months M Positive sweat test ?

In reference to DF508 and 1716G>A. Does this mean these two mutation have resulted in "classic CF"? Does this mean 1716G>A is disease causing?
Gibson75 on 2013-08-12 07:00:25

Login to comment 75 ABCC7 p.Pro67Leu ABCC7 p.Trp846* Dx of CF, pancreatic insufficiency, frequent colds and cough 4 DF508/p.P67L 3 months F Positive sweat test 50, 53, 60 Followed in CF Clinic 5 DF508/p.W846X 9 months M Positive sweat test ? Login to comment 76 ABCC7 p.Trp1282* ABCC7 p.Arg1158* ABCC7 p.Gly576Ala ABCC7 p.Leu997Phe ABCC7 p.Ser492Phe ABCC7 p.Val562Ile ABCC7 p.Arg352Trp ABCC7 p.Arg352Trp ABCC7 p.Val358Ile Meconium peritonitis;pseudocyst; volvulus 6 p.W1282X/p.S492F 2 months M IRT positive 57, 78, 75, 80, 81 Dx of CF, symptomatic 7 DF508/p.F1099Lb 2 months M IRT positive 48, 52 Asymptomatic at this point 8 DF508/[p.R352W; pP750L]c 1.5 months M IRT positive 1 nl, 44 Followed in CF clinic, being treated prophylactically, neg. elastase 9 DF508/c.1154insTC 4 days M Meconium ileus at birth Not done CF, two affected sibs 10 DF508/c.2789+2insA 2 months F IRT positive 58,57,53 Dx of CF a Concentrations >60 mmol/l on repeated analysis are diagnostic for cystic fibrosis b Novel CFTR mutation c Complex CFTR allele with two different mutations Table 4 Complex CFTR alleles observed in a series of 157 patient samples after extensive sequencing Subject Genotype Phenotype Age Sweat chloride concentration (mmol/l) 1 [p.G576A;p.R668C]/wta Chronic cough, sinusitis, and recurrent pneumonia 3 years Normal 2 p.R1158X/[p.V562I;p.A1006E] Mild CF 40 years 115 3 DF508/[p.R352W;p.P750L] Abnormal newborn screen 49 days 44 4 [c.1198_1203delTGGGCT;c.1204G>A]/wt Mild CF (respiratory symptoms) 12 years 110, 115 a This complex allele has been previously described in a patient with disseminated bronchiectasis with L997F on the other allele (Pignatti et al. 1995) Table6NovelCFTRvariantsfoundinaseriesof157patientsamplesafterextensivesequencing SubjectMutation type LocationNucleotidechangeEffectonproteinCFTRdomaina Mutationonother allele Phenotype 1MissenseExon4c.605G>Cp.S158TL1Nonedetected4-month-oldmale,abnormalnewbornscreen; 3borderlinesweattestresults 2ComplexalleleExon7[c.1198_1203delTGGGCT; c.1204G>A] [p.W356_A357del; p.V358I] AfterTM6and beforeNBD1 Nonedetected12-year-oldmale,meconiumilleusatbirth, respiratorysymptomsofCF;positivesweatchlorides (110,115mmol/l).Motheralsocarriescomplexallele 3MissenseExon9c.1484G>Tp.G451VNBD1DF50819-year-oldmale,diagnosisofCF 4MissenseExon10c.1573A>Gp.K481ENBD1Nonedetected15-year-oldmale,atypicalCF,asthma,2borderline sweatchlorides(low60s) 5MissenseExon10c.1604G>Cp.C491SNBD1NonedetectedNoabnormalsymptoms;sisterofCFpatientthat carriesp.P67L/DF508.Probablebenign variantascertainedduring singleexonsequencingofexon10 6DeletionExon10c.1641AG>Tp.K503NfsX23NBD1p.H609R22-year-oldmale,classicCF,PI,positivesweat chloride(>100mmol/l) 7DeletionExon15c.2949_2953delTACTCp.H939fsX32L3DF5083-month-oldfemale,diagnosisofCF,positivesweat chloride(105mmol/l) 8MissenseExon15c.2978A>Tp.H949LL3Nonedetected, but5Tpositive 12-year-oldmale,atypicalCF,sinusproblems. Login to comment 79 ABCC7 p.Val358Ile complex allele ([p.W356_A357del; p.V358I]) was 12 years old and had respiratory symptoms of CF and elevated sweat chloride values. Login to comment 81 ABCC7 p.Phe1099Leu ABCC7 p.Thr1036Asn ABCC7 p.Gly451Val Of the seven novel missense mutations ascertained, we expect that three (p.G451V, p.T1036N, and p.F1099L) are disease-associated mutations. Login to comment 82 ABCC7 p.Phe1099Leu ABCC7 p.Gly451Val Two of these missense mutations (p.G451V, p.F1099L) were found in patients with a clinical diagnosis of CF and carrying the Delta F508 mutation on the other allele. Login to comment 83 ABCC7 p.Thr1036Asn The p.T1036N missense mutation in exon 17 is expected to be disease-associated since it was found in a 14-year-old male Hispanic with classic CF. Login to comment 84 ABCC7 p.Thr1036Asn Homozygosity for p.T1036N in this patient was confirmed by sequencing DNA from parental blood samples; each parent was a heterozygous carrier. Login to comment 86 ABCC7 p.Ser158Thr ABCC7 p.Lys481Glu ABCC7 p.His949Leu Three novel missense mutations (p.S158T, p.K481E and p.H949L) are consistent with being disease-associated alleles, but the evidence for this was not as strong as for the three previously mentioned. Login to comment 89 ABCC7 p.His949Leu ABCC7 p.His949Leu One patient (p.H949L/wt) was positive for the 5T variant in intron 8 polyT locus, but the parental samples were not available to ascertain if the 5T allele was on the same or opposite chromosome as the p.H949L mutation. Login to comment 92 ABCC7 p.Cys491Ser The p.C491S missense mutation is expected to be a benign variant since it was ascertained during single exon sequencing in an unaffected sibling of a CF patient. Login to comment 95 ABCC7 p.Cys491Ser The PolyPhen prediction tool also suggests that p.C491S is a benign variant (Table 7). Login to comment 97 ABCC7 p.Ser158Thr The only exception is for the missense mutation p.S158T found within L1 domain of CFTR. Login to comment 103 ABCC7 p.Arg1158* ABCC7 p.Ala1006Glu ABCC7 p.Val562Ile The last two samples were from affected siblings and were found to be positive for three previously described CFTR mutations: p.V562I, p.A1006E, and p.R1158X. Login to comment 120 ABCC7 p.Ser158Thr The one exception was for the p.S158T mutation that we believe to be disease associated. Login to comment