Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism.
OBJECTIVE
Cystic fibrosis (CF; OMIM# 219700) is caused by mutation in the CF transmembrane regulator (CFTR) gene. We investigate whether the (paternal) M348K mutation is a benign polymorphism or a disease-causing mutation in a patient clinically affected with CF, with the second (maternal) CFTR allele identified as N1303K.


METHODS
The patient and his father were studied for the presence of mutations in the CFTR gene using the DHPLC system to analyze all CFTR exons. Amplicons showing an abnormal elution profile were sequenced.


RESULTS
The CFTR gene from the healthy father has two mutations, M348K and G1244E. The affected son inherited only the G1244E paternal mutation from his father, and hence the two paternal mutations are trans and do not occur in the same CFTR gene. The patient's genotype is G1244E(paternal)/N1303K(maternal). This information was used to study an ongoing pregnancy of the couple, where the fetus inherited the same genotype as the affected proband and therefore is affected.


CONCLUSIONS
M348K in the CFTR gene is not a mutation causing CF, but a rare polymorphism. These data are important for genetic counseling and prenatal diagnosis and illustrate the importance of full sequence data when studying rare mutations.
D'Apice
Maria Rosaria
MR
Department of Biopathology and Imaging Diagnostic, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy.
Gambardella
Stefano
S
Russo
Silvia
S
Lucidi
Vincenzina
V
Nardone
Anna Maria
AM
Pietropolli
Adalgisa
A
Novelli
Giuseppe
G
D000483:Alleles; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator