The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis.
OBJECTIVE
To determine whether intragenic changes modulate the cystic fibrosis (CF) phenotype in individuals who are positive for the I148T allele.


METHODS
The genes from individuals who carried at least one copy of the I148T allele were analyzed for additional changes that may be acting as genetic modifiers.


RESULTS
Seven of eight individuals with a known or suspected diagnosis of CF who carried I148T in combination with a severe CF mutation also carried 3199del6. Eight apparently healthy adult individuals who were compound heterozygous for I148T and a severe CF mutation or homozygous for I148T did not carry the deletion ( = 0.0014). The I148T allele occurs on at least three haplotypes: an IVS-8 9T background, a 7T background, or a 9T + 3199del6 background. The 3199del6 allele was not identified in 386 non-CF chromosomes.


CONCLUSIONS
It is concluded that I148T occurs on at least three haplotypes and the complex allele I148T + 9T + 3199del6 is associated with a classic CF phenotype.
Rohlfs
Elizabeth M
EM
Genzyme Genetics, Molecular Diagnostic Laboratory, Framingham, Massachusetts 01701, USA.
Zhou
Zhaoqing
Z
Sugarman
Elaine A
EA
Heim
Ruth A
RA
Pace
Rhonda G
RG
Knowles
Michael R
MR
Silverman
Lawrence M
LM
Allitto
Bernice A
BA
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D015870:Gene Expression; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator