PEDIATRICS Vol. 100 No. 3 September 1997, p. e5
Copyright ©1997 by the American Academy of Pediatrics

ELECTRONIC ARTICLE:
A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype

Received Jan 10, 1997; accepted Mar 13, 1997.

Eitan Kerem^*, Malka Nissim-Rafinia, Zvi Argaman^*, Arie Augarten^§, Lea Bentur, Aharon Klar^¶, Yaacov Yahav^§, Amir Szeinberg^§, Ornit Hiba, David Branski^*, Mary Corey^#, and Batsheva Kerem

From the ^* Department of Pediatrics, Cystic Fibrosis (CF) Clinic, Shaare Zedek Medical Center, Jerusalem, Israel; and the  Department of Genetics, Hebrew University, Jerusalem; the ^§ Department of Paediatrics, CF Clinic, Chaim Sheba Medical Center, Tel Hashomer, Israel; the  Department of Paediatrics, CF Clinic, Rambam Medical Center, Haifa; the ^¶ Department of Paediatrics, Bikur Cholim Hospital, Jerusalem, Israel; and the ^# Research Institute, Hospital for Sick Children, Toronto, Canada.

Objective.  Cystic fibrosis (CF) has variable clinical presentation. Disease severity is partially associated with the type of mutation. The aim of this study was to report genotype-phenotype analysis of the G85E mutation.

Patients.  The phenotype of 12 patients (8 were from the same extended family, and 5 of them were siblings from 2 families) carrying at least one copy of the G85E mutation was evaluated and compared with the phenotype of 40 patients carrying the two severe mutations, W1282X and/or F508 (group 1), and with 20 patients carrying the splicing mutation, 3849+10kb C->T, which was found to be associated with milder disease (group 2).

Results.  A high phenotypic variability was found among the patients carrying the G85E mutation. This high variability was found among patients carrying the same genotype and among siblings. All the studied chromosomes carrying the G85E mutation had the 7T variant in the polythymidine tract at the branch/acceptor site in intron 8. Of the G85E patients, 25% had pancreatic sufficiency and none had meconium ileus, compared with 0% and 32%, respectively, of patients from group 1, and 80% and 0%, respectively, from group 2. Two patients carrying the G85E mutation had sweat chloride levels <60 mmol/L whereas all the others had typically elevated levels >80 mmol/L. Compared with group 2, patients carrying the G85E mutation were diagnosed at an earlier age and had higher sweat chloride levels, with mean values similar to group 1 but significantly more variable. Forced expiratory volume in 1 second (FEV₁) was similar in the three groups, with no differences in the slope or in age-adjusted mean values of FEV₁. The levels of transcripts lacking exon 9 transcribed from the G85E allele measured in 3 patients were 55%, 49%, and 35% and their FEV₁ values were 82%, 83%, and 50% predicated, respectively.

Conclusions.  The G85E mutation shows variable clinical presentation in all clinical parameters. This variability could be seen among patients carrying on the other chromosome the same CFTR mutation, and also among siblings. This variability is not associated with the level of exon 9 skipping. Thus, the G85E mutation cannot be classified either as a severe or as a mild mutation.

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