Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: Results from a collaborative study

Abstract

Purpose: We expect that the mutation panel currently recommended for preconception/prenatal CF carrier screening will be modified as new information is learned regarding the phenotype associated with specific mutations and allele frequencies in various populations. One such example is the I148T mutation, originally described as a severe CF mutation. After implementation of CF population-based carrier screening, we learned that I148T exists as a complex allele with 3199del6 in patients with clinical CF, whereas asymptomatic compound heterozygotes for I148T and a second severe CF mutation were negative for 3199del6. Methods: We performed reflex testing for 3199del6 on 663 unrelated specimens, including I148T heterozygotes, compound heterozygotes, and a homozygous individual. Results: Less than 1% of I148T carriers were also positive for 3199del6. Excluding subjects tested because of a suspected or known CF diagnosis or positive family history, 0.6% of I148T-positive individuals were also positive for 3199del6. We identified 1 I148T homozygote and 6 unrelated compound heterozygous individuals with I148T and a second CF variant (2 of whom also carried 3199del6). In addition, one fetus with echogenic bowel and one infertile male were heterozygous for I148T (3199del6 negative). Conclusions:Reflex testing for 3199del6 should be considered whenever I148T is identified. Reflex testing is of particular importance for any symptomatic patient or whenever one member of a couple carries a deleterious CF mutation and the other member is an I148T heterozygote. Further population data are required to determine if I148T, in the absence of 3199del6, is associated with mild or atypical CF or male infertility. Genet Med 2004:6(5):421-425. Key Words: cystic fibrosis, mutation analysis, 3199del6, I148TOver 1000 cystic fibrosis (CF) mutations have been identified; most are rare, having been detected in only one family. 1 In 2001, the ACMG 2 and ACOG 3 developed a panethnic panel of 25 common mutations with a frequency Ն 0.1% in the general population and recommended that all Caucasians who are either pregnant or considering pregnancy be screened. ACMG/ ACOG also recommend that screening be made available to individuals in lower risk ethnic groups. We expect that the mutation panel will be modified as new information arises regarding the phenotype associated with specific mutations and allele frequencies in various populations. The I148T mutation, which is currently included in the panel, was first reported in 1990 as a severe mutation 4 -7 and accounted for 9% of FrenchCanadian CF mutations. 8 After implementation of CF population-based carrier screening, two studies noted a Ͼ 100-fold increase in the frequency of I148T among individuals undergoing carrier screening compared to patients with clinical CF. 9 -10 Further studies revealed a second mutation, 3199del6, in-cis with I148T in affected patients, 9,11 a finding previously reported in 1998. 1 The 3199del6 mutation was not present in asymptomatic compound heterozygous individuals w...

Mutation-Specific Potency and Efficacy of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Potentiators

“…This behavior is inconsistent with the latter mutations being causative of CF and suggests that they are instead benign CFTR variants. In fact, it has been shown that I148T is in linkage disequilibrium with a deletion of two amino acids (3199del6) localized more distantly toward the carboxyl terminus (Rohlfs et al, 2002;Monaghan et al, 2004) and that this latter sequence change is the one causing CFTR loss of function. I175V may be another benign variant because its activity was comparable with or even higher than that of the native protein.…”

Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians

“…Altogether, our observations further demonstrate that the 3199del6 mutation is associated with a classical pancreatic insufficiency CF phenotype, consistent with the suggestion of Buyse et al 7 Previous studies have identified 3199del6 in 1.8%, 0.9%, and 0.6% of I148T heterozygous carriers and determined the frequency of 3199del6 in the general North American population to be Ͻ 0.1%, below the frequency threshold criteria for inclusion in the ACMG CF mutation screening panel. 1,8,9 In this study, we report a 2.2% frequency for the 3199del6 mutation among French Canadian CF chromosomes. As mentioned, only two I148T carriers (one Lebanese and one of unknown origin) tested negative for the 3199del6 mutation in our cohort of 32 unrelated I148T individuals.…”

Pancreatitis in Cystic Fibrosis and CFTR-Related Disorder

“…Consequently, alternative and simpler direct pancreatic stimulation techniques (non-quantitative), are used at many clinical centers. These generally utilise a single-lumen duodenal tube or endoscope to aspirate duodenal pancreatic secretions, either as a spot sample and/or over a timed sampling period (Choi et al, 2001;Monaghan et al, 2004;Rohlfs et al, 2002;Suaud et al, 2007). Despite their popularity, non-quantitative techniques have a high false positive rate for misdiagnosing PI and have not been proven superior over non-invasive indirect pancreatic function tests.…”