Clin Genet

Complete identification of cystic fibrosis transmembrane conductance regulator mutations in the CF population of Saguenay Lac-Saint-Jean (Quebec, Canada).

Year 1998
De Braekeleer M. Mari C. Verlingue C. Allard C. Leblanc JP. Simard F. Aubin G. Ferec C.
Departement des Sciences Humaines, Universite du Quebec a Chicoutimi, Hopital de Chicoutimi, Canada.
Over the past few years, we have conducted a systematic study of 230 cystic fibrosis (CF) chromosomes in the Saguenay Lac-Saint-Jean (SLSJ) population which has a high CF incidence (1/936 live births). We identified 11 mutations accounting for 100% of the CF chromosomes found in patients born in SLSJ. Our results indicate that denaturing gradient gel electrophoresis (DGGE) is a powerful method of identifying CF mutations. They have also considerable implications for genetic counselling and molecular characterization of doubtful patients. They make carrier screening technically feasible in this population.

The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies.

Year 1998
Brock DJ. Gilfillan A. Holloway S.
Human Genetics Unit, The University of Edinburgh, Molecular Medicine Centre, Western General Hospital, UK.
The incidence of cystic fibrosis (CF) has previously been calculated from epidemiological surveys and from neonatal screening. With the cloning of the CF gene it has become possible to derive incidence figures from heterozygote frequencies, provided that the distribution of mutant alleles among healthy carriers is the same as among affected people. We have estimated the allele frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360 unselected women undergoing antenatal heterozygote screening. The proportion of R117H, an allele of known mild effect, was much greater for heterozygotes than for homozygotes. The incidence of CF was therefore calculated from the heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161 successively screened women. The point estimate for the incidence of CF in the Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to 1 in 2336.

Severe cystic fibrosis associated with a deltaF508/R347H + D979A compound heterozygous genotype.

Year 1998
Hojo S. Fujita J. Miyawaki H. Obayashi Y. Takahara J. Bartholomew DW.
First Department of Internal Medicine, Kagawa Medical University, Japan.
This report is concerned with twins with cystic fibrosis (CF). They are of mixed parentage: Japanese mother and German father. One case is presented with meconium ileus as a neonate. The other patient did relatively well until the age of 6 years when she was first hospitalized and diagnosed with pulmonary aspergillosis. They have been receiving standard therapies for CF including digestive enzymes, vitamins and periodic antibiotic therapy in the US. At 19 years of age, they were tested for common mutations and one AF508 cystic fibrosis transmembrane conductance regulator (CFTR) allele was found. Further testing of their CFTR gene as well as those of their Japanese mother and grandmother revealed missense mutations in exon 7 (R347H) and exon 16 (D979A). Although the D979A mutant is very rare, this mutation combination seemed to be responsible for severe CF phenotypes.

DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLH1) in 34 Swedish families with colorectal cancer.

Year 1998
Liu T. Wahlberg S. Rubio C. Holmberg E. Gronberg H. Lindblom A.
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited syndrome which confers an increased risk for colorectal cancer and endometrial cancer as well as other tumors. It is caused by germline DNA mismatch repair (MMR) gene mutations in five MMR genes, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6. Finding mutations in these high risk families means that you can offer presymptomatic carrier diagnosis and thereby identify individuals with a very high risk for cancer. These persons benefit from counseling and should be offered surveillance. We have used DGGE to screen members from 34 families for mutations in hMLH1 and hMSH2. Six mutations in five families were found, five of these mutations are new. Besides, three new polymorphisms were identified. The mutations were found in two of seven Amsterdam criteria HNPCC families and in three of four families with at least one case of early onset of CRC (before 35), suggesting there are appropriate families to be chosen for mutation screening in MMR genes.

Detection of mtDNA deletion in Pearson syndrome by two independent PCR assays from Guthrie card.

Year 1998
Toth T. Bokay J. Szonyi L. Nagy B. Papp Z.
I. Department of Obstetrics and Gynaecology, Semmelweis University Medical School, Budapest, Hungary. toma@noi1.sote.hu
Pearson syndrome is a multisystem juvenile condition associated with deletions in the mitochondrial genome. The most common 4977 bp deletion of mitochondrial DNA (mtDNA) can mainly be detected in the patients' peripheral blood. Here we report a child with a clinically unclarified diagnosis where molecular genetic results proved Pearson syndrome from stored dried blood sample 6 months after the patient's death. PCR amplification around the breakpoint of the most common mtDNA deletion could detect the presence of mutated mtDNA. Another polymerase chain reaction (PCR) assay indicated the low level of wild type mtDNA in patients' blood. We believe that this case shows the importance of storing Guthrie card and the availability of detection of Pearson syndrome from dried blood sample.