ABCMdb

PMID: 22194755

Cole KH, Sosnay PR, Yarmus LB, Zuckerman JB
The Novel CFTR Mutation A457P in a Male with a Delayed Diagnosis of Cystic Fibrosis.
Case Report Med. 2011;2011:903910. Epub 2011 Dec 13., [PubMed]

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0 ABCC7 p.Ala457Pro Hindawi Publishing Corporation Case Reports in Medicine Volume 2011, Article ID 903910, 4 pages doi:10.1155/2011/903910 Case Report The Novel CFTR Mutation A457P in a Male with a Delayed Diagnosis of Cystic Fibrosis Kate H. Cole,1 Patrick R. Sosnay,1 Lonny B. Yarmus,1 and Jonathan B. Zuckerman2 1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 East Monument Street, 5th Floor, Baltimore, MD 21208, USA 2 Division of Pulmonary and Critical Care Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102, USA Correspondence should be addressed to Jonathan B. Zuckerman, zuckej@mmc.org Received 16 August 2011; Revised 21 September 2011; Accepted 25 September 2011 Academic Editor: Mamede de Carvalho Copyright (c) 2011 Kate H. Cole et al. Login to comment 5 ABCC7 p.Ala457Pro ABCC7 p.Ala457Pro We subsequently performed testing, which revealed a previously unreported mutation: A457P (p.Ala457Pro, c.1369G>C). Login to comment 7 ABCC7 p.Ala457Pro The A457P mutation appears to confer a relatively mild phenotype, as is usually observed with CFTR class IV-VI defects. Login to comment 14 ABCC7 p.Ala457Pro After transfer of care to our institution, a full-sequence CFTR genetic analysis was performed by Ambry Genetics, which revealed an A457P mutation in combination with the F508 deletion. Login to comment 15 ABCC7 p.Ala457Pro We briefly describe the clinical profile of this patient with the A457P mutation, discuss the established criteria used to diagnose CF, and speculate about the possibility that this newly identified variant is a disease-causing mutation. Login to comment 49 ABCC7 p.Ala457Pro Testing revealed an A457P mutation in exon 10 in combination with the F508 deletion. Login to comment 51 ABCC7 p.Ala457Pro A literature review and examination of the Sick Kids Cystic Fibrosis Mutation database revealed no prior report of the A457P mutation [10]. Login to comment 69 ABCC7 p.Ala457Pro Analysis of the previously unidentified genetic variation A457P must be considered in the context of its discovery in an individual with an established diagnosis of CF. Login to comment 75 ABCC7 p.Ala457Pro Given that CF is an autosomal recessive disease and that our patient is an affected individual, it would appear that A457P is a CF-causing mutation in this instance. Login to comment 78 ABCC7 p.Ala457Pro Therefore, it is possible, although unlikely, that another mutation is present on the A457P chromosome, for example, in an intronic region that may not have been sequenced. Login to comment 79 ABCC7 p.Ala457Pro When entered into publicly available in silico mutation prediction tools PolyPhen [13] and SIFT [14], the A457P mutation, which resides within the nucleotide binding domain 1 of the CFTR, was predicted to be deleterious; however, these methods have not shown adequate sensitivity or specificity in CF to have clinical utility [15]. Login to comment 80 ABCC7 p.Ala457Pro Taken together, these findings argue for A457P being a disease-causing mutation, though it is still most accurate to formally categorize it as a VUS. Login to comment 90 ABCC7 p.Ala457Pro Our patient`s presentation of mild respiratory symptoms and pancreatic sufficiency in association with one known Class II mutation suggests that A457P is likely a Class IV-VI mutation (i.e., one that retains some chloride channel function). Login to comment 91 ABCC7 p.Ala457Pro Functional testing could help elucidate the cellular consequences of the A457P substitution to support the hypothesis that the mutation is deleterious and to assign the mutation to a functional class; however, the considerable resources necessary to perform such confirmatory work would generally make this impractical for a mutation found in a single patient. Login to comment 94 ABCC7 p.Ala457Pro Detailed genetic analysis revealed that he carries the novel mutation (A457P) along with the most common CFTR mutation (F508del). Login to comment