ABCMdb

PMID: 19092437

Moskowitz SM, Chmiel JF, Sternen DL, Cheng E, Gibson RL, Marshall SG, Cutting GR
Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders.
Genet Med. 2008 Dec;10(12):851-68., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* Pulmonary disease is the major cause of morbidity and Table 1 Classification scheme for CFTR mutations112 Mutation class Effect on CFTR protein Mechanisms I Reduced or absent synthesis Nonsense, frameshift, or splice junction mutations II Block in protein processing Missense mutations or amino acid deletions III Block in regulation of CFTR chloride channel Missense mutations IV Altered conductance of CFTR chloride channel Missense mutations V Reduced amounts of functioning CFTR protein Missense or splice junction mutations Table 2 Phenotypes of 10 most common CFTR alleles in whites with CF41 Mutation Relative frequency (%)a Functional classb Phenotypec ⌬F508 66.0 II Classic G542X 2.4 I Classic G551D 1.6 III Classic N1303K 1.3 II Classic W1282X 1.2 I Classic R553X 0.7 I Classic 621ϩ1GϾT 0.7 I Classic 1717-1GϾA 0.6 I Classic R117H 0.3 IV Nonclassic R1162X 0.3 Not cleard Classic a Calculated using total CFTR alleles as the denominator. Login to comment 56 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr Liver disease is second to pulmonary disease (plus organ transplantation complications) as a cause of mortality in CF (1.7% of deaths).26 Table 3 Core mutation panel carrier recommended by the ACMG for routine CF diagnostic testing and carrier screening of the general population7 Intronic mutations Exonic mutations Missense Nonsense In-Frame Deletion 621ϩ1GϾT G85E G542X ⌬I507 711ϩ1GϾT R117H R553X ⌬F508 1717-1GϾA R334W R1162X 1898ϩ1GϾA R347P W1282X 2184delA A455E 2789ϩ5GϾA G551D 3120ϩ1GϾA R560T 3659delC N1303K 3849ϩ10kbCϾT Endocrine manifestations of CF CF-related diabetes mellitus (CFRDM) may present in adolescence. Login to comment 98 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu For example, compound heterozygotes with ⌬F508/A455E have better pulmonary function than individuals who are homozygous for ⌬F508.10 In individuals with one or two R117H mutations, the severity of lung disease depends on the presence of a variation in the poly T tract of intron 8.44,45 Individuals with the 5T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation usually develop the lung disease of CF; but those individuals with the 7T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation have a highly variable phenotype, which can range from no symptoms to mild lung disease (Table 4).44,46 Because the A455E and R117H mutations are associated with pancreatic sufficiency, the less severe lung disease seen in individuals with these mutations could be the consequence of better nutritional status. Login to comment 99 ABCC7 p.Arg117His CAVD usually results from the combination of one severe CFTR mutation on one chromosome with either a mild CFTR mutation or the 5T allele (even in the absence of R117H) on the other chromosome (Table 5). Login to comment 104 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu The mechanism of partial penetrance of the 5T allele for CAVD is due to variation in the length of the adjacent TG tract (estimated at 60% in one study).50,51 Thus, interpretation of the disease implications of the 5T variant requires assessment of the number of TG repeats adjacent to the polythymidine tract.51 DIAGNOSIS AND TESTING Clinical phenotype Phenotypic features of CF include but are not limited to the following: ● Chronic suppurative sinopulmonary disease, with chronic coughandsputumproduction,chronicwheezeandairtrap- ping, obstructive lung disease on lung function tests, persistent colonization with pathogens commonly found in individuals with CF, chronic chest radiograph abnormalities, chronic pansinusitis, and/or digital clubbing Table 5 Proportion of CFTR genotypes detected in men with CAVD, based on pooled data4,47,57,116 Allele 1 Allele 2 Proportion (%)a 5T 5T 2 Other than 5T Other than 5T 26 5T Other than 5T 26 5T Wild type 8 Other than 5T Wild type 17 Wild type Wild type 22 a Percentages total to Ͼ100% because of rounding Table 4 CFTR genotype-phenotype correlations41,44,50,51,57,114-116 Allele 1 Allele 2 Range of phenotypes Classica Classic Classic ϾϾ nonclassic Milda Classic or mild Nonclassic Ͼ classic R117H/5T Classic or mild Nonclassic Ͼ classic R117H/7T Classic or mild Asymptomatic female or CAVD Ͼ nonclassic 5T/TG13 or TG12 Classic or mild CAVD or nonclassic CF ϾϾ asymptomatic carrier 5T/TG11 Classic or mild Asymptomatic Ͼ CAVD 7T or 9T Classic or mild Asymptomatic 7T or 9T 7T or 9T Asymptomatic a Classic refers to Class I, II, and III mutations (e.g., ⌬F508); mild refers to Class IV and V mutations (e.g., A455E) exclusive of R117H and 5T alleles (see Table 1). Login to comment 152 ABCC7 p.Arg117His ABCC7 p.Arg117His The 5T variant decreases the efficiency of intron 8 splicing.72 If an individual with R117H also has the 5T allele, family studies are recommended to determine if the 5T allele is in cis configuration or trans configuration with the R117H allele. Login to comment 155 ABCC7 p.Ile148Thr A longer TG tract (12 or 13) in conjunction Table 7 Molecular genetic testing used in CFTR-related disorders Test method Mutations detected Population Mutation detection rate (%) Targeted mutation analysis117,118 CFTR mutations using the original 25-mutation panela Ashkenazi Jewish 97 Non-Hispanic white 88.3 African American 69 Hispanic American 57 Asian American Unknown Sequence analysis73 CFTR sequence variantsb All groups 98.7 Deletion analysis CFTR exonic and whole gene deletions All groups Unknown a The original 25-mutation panel recommended by the ACMG includes the mutations listed in Table 3 as well as 1078delT and I148T.117 The 23-mutation panel recommended in 2004 is expected to have a similar mutation detection rate.7 Other panels may have significantly different mutation detection rates. Login to comment 156 ABCC7 p.Arg117His b Detection is based on re-sequencing of all coding sequences, splice donor and acceptance sites, the promotor region and two intronic sequences.73 with a shorter poly T tract (5T) has the strongest adverse effect on proper intron 8 splicing.50,51 5T/TG tract analysis should not be included in a routine carrier screen, but is appropriate as a reflex test when an R117H mutation is detected. Login to comment