Fernand Simard

Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation

Abstract Cystic fibrosis (CF) has a high incidence in the French-Canadian population of Saguenay Lac-Saint-Jean (Quebec). The A455E mutation accounts for 8.3% of the CF chromosomes. This mutation was shown to be associated with a milder lung disease in the Dutch population. Twenty two CF patients distributed in 17 families and compound heterozygotes for the A455E mutation have been followed at the Clinique de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the ΔF508 mutation while the remaining eight patients had the 621+ 1G→T mutation. Each patient was matched by sex and age to a patient homozygous for the ΔF508 mutation. The pairs were analyzed for several clinical and laboratory variables. The A455E compound heterozygotes were diagnosed at a later age (P = 0.003) and had chloride concentrations at the sweat test lower than those homozygous for the ΔF508 mutation (P = 0.007). More patients were pancreatic sufficient (P = 0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary function tests (P < 0.02). CF patients compound heterozygous for the A455E mutation have a milder pancreatic and lung disease than the ΔF508 homozygotes. Therefore, the A455E should be associated with a better prognosis.

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

Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St-Jean (Quebec, Canada)

Cystic fibrosis (CF) is an autosomal recessive disorder with a prevalence at birth estimated at 1/2000–1/2500 livebirths in Caucasian populations. Some 127 CF individuals are known in Saguenay‐Lac‐St‐Jean (SLSJ), a geographically isolated region of Quebec. The prevalence at birth was estimated at 1/902 live borns, and the carrier rate was estimated at 1/15 inhabitants in the SLSJ region. The mean inbreeding coefficient was only slightly elevated in the CF group compared with three control groups, and was due to remote consanguinity. The mean kinship coefficient was 2.4 times higher in the CF group than in the control groups. In SLSJ region, the places of origin of the CF individuals and their parents did not show a clustered nonuniform distribution. Endogamy was not higher in the CF group than in control groups.

Disease knowledge in a high-risk population for cystic fibrosis

Cystic fibrosis (CF) has high incidence (1/936 live births) and carrier rate (1/15 inhabitants) in Saguenay-Lac-Saint-Jean (SLSJ). One objective of a major enquiry among several subsets of individuals from this high-risk population for CF was to evaluate the knowledge of the disease and its genetic transmission. The overall score of correct answers pertaining to the clinical signs of CF among medical doctors (general practitioners and specialists) was 42.2 and 65.6%, respectively; it was 84.2% for questions regarding the genetic transmission of CF. The knowledge of the clinical signs was reasonable among CF patients and their parents (about 65% of correct answers), but it was much higher for the genetics (over 88% among parents). Aunts and uncles of CF children were poorly informed of the clinical signs (33.9% of correct answers) but well informed of the genetic transmission (73.8%). Specific subsets of the SLSJ population showed important gaps in the knowledge of the clinical signs of CF but, overall, they were well informed of its genetic transmission.

Genealogy and geographical distribution of CFTR mutations in Saguenay Lac-Saint-Jean (Quebec, Canada)

Saguenay Lac-Saint-Jean (SLSJ), a region located in northeastern Quebec, has a high incidence of cystic fibrosis (CF). During the past few years the majority of the CF patients have been genotyped. The geographical distribution of the birth places of the patients and obligate carriers of the 621 + 1G-->T, the A455E and the delta F508 mutations (which accounted for 89% of the CF chromosomes) showed differences that can be explained by some degree of isolation but also by differential migration. The mean inbreeding and kinship coefficients were higher among the various CFTR mutation groups than in the general population. An ancestor couple common to most of the A455E carriers was identified. These data further substantiate the role of founder effect in the CF population of SLSJ.

Phenotypic heterogeneity in CF sibs compound heterozygous for the G85E and 621 + 1G→T mutations

To the Editor: The recent publication of a letter reporting phenotypic intrafamilial heterogeneity in an Italian cystic fibrosis (CF) family (Borgo et al. 1993) prompted us to report another family with an uncommon genotype in which two affected sisters showed phenotype heterogeneity. We also show that, based on a single case report, it is difficult to assess whether a CF mutation is mild or severe. Although several studies have analyzed the relationship between phenotype and genotype, using several combinations, few studies have been conducted on intrafamilial phenotypic variation since the cystic fibrosis transmembrane regulator (CFTR) gene has been identified. During a survey of the CFTR mutations in a cohort of 91 families from Saguenay-Lac-Saint-Jean, the G85E mutation was found in only one family (two sisters) in association with the 621 + 1G+T mutation (Zielenski et al. 1991, Rozen et al. 1992). The phenotypic characteristics of both sisters are presented in Table 1. Both sisters had pancreatic insufficiency (determined by fecal-fat balance studies). However, only sister no. 2 presented with meconium ileus and experienced several episodes of intestinal subocclusion and meconium ileus equivalent. Liver cirrhosis was diagnosed when she was 15 years old and is believed to be a consequence of cystic fibrosis. Her clinical course deteriorated due to her liver condition, including portal hypertension, splenomegaly, esophageal varices and hemorrhages of the upper intestinal tract, of which she eventually died at 18 years of age. Both sisters experienced several episodes of bronchopneumonia and colonization by Pseudomonas aeruginosa. However, the respiratory function test (FVC, FEY FEF) results remained Received 15 November 1993, revised version received 7 April, accepted for publication 4 May I 1994

CORRELATION OF SWEAT CHLORIDE CONCENTRATION WITH GENOTYPES IN CYSTIC FIBROSIS PATIENTS IN SAGUENAY LAC-SAINT-JEAN, QUEBEC, CANADA

OBJECTIVES Saguenay Lac-Saint-Jean, a geographically isolated region of northeastern Quebec has a high incidence of cystic fibrosis (CF) and three mutations only account for 94% of the CF chromosomes. The objective of the present study was to determine whether different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene had different effects upon the sweat chloride concentration. DESIGN AND METHODS The sweat chloride concentration of 114 patients was measured by quantitative pilocarpine iontophoresis. RESULTS CF patients carrying the A455E mutation, usually associated with pancreatic sufficiency, had lower sweat chloride concentrations than those carrying mutations associated with pancreatic insufficiency (delta F508 and 621 + 1G-->T). CONCLUSIONS Our results confirm that mutations resulting in a reduction of the chloride current at the apical membrane of epithelial cells induce lower sweat chloride values. However, there are differences in the chloride current between genotypes, even if they are composed of mutations apparently having the same functional effect.

Reproductive attitudes of couples having a child with cystic fibrosis in Saguenay–Lac-Saint-Jean (Quebec, Canada)

Cystic fibrosis (CF) has a high incidence (1/936 live births) and carrier rate (1/15 inhabitants) in Saguenay-Lac-Saint-Jean. One objective of a major enquiry among several subsets of individuals from this high-risk population for CF was to evaluate the reproductive behaviour of couples with a CF child attending the comprehensive CF clinic in Chicoutimi. The knowledge of the recurrence risk resulted in deciding against further progeny or in reducing the number of children. More reliable contraception methods after the birth of the CF child, but not prenatal diagnosis, were used. Although a minority of parents with a CF child would abort a CF foetus, they apparently started viewing pregnancy interruption for CF after prenatal diagnosis as an acceptable reproductive option.

Genetic determinants of Pseudomonas aeruginosa colonization in cystic fibrosis patients in Canada.

The present study was aimed at analyzing whether the rate of colonization and the age at colonization withPseudomonas aeruginosa was genetically determined in cystic fibrosis (CF) patients. These two variables were calculated among 127 CF patients whose genotypes were known and who were monitored at the Clinique de Fibrose Kystique in Saguenay Lac-Saint-Jean. No statistically significant differences were found in the rate or the age at colonization when the patients were grouped by genotype; however, this result could be due to the small number of patients in each genotype group. The rate of colonization was significantly lower among CF patients carrying the A455E mutation, a “mild” allele with respect to exocrine pancreatic function, than among those carrying either the ΔF508 or the 621+1G->T mutation, both of which are “severe” alleles. The results confirm previous reports that the rate of colonization withPseudomonas aeruginosa is, at least in part, genetically determined.

Birth distribution in cystic fibrosis in Saguenay-Lac-St-Jean, Quebec, Canada.

Although a seasonal trend in the birth distribution has been reported in cystic fibrosis (CF), this finding is still very controversial. The birth distribution of 113 patients with cystic fibrosis born in Saguenay-Lac-St-Jean (complete ascertainment) was analysed using two different statistical methods. Our results showed no monthly or seasonal birth variation. It is likely that a bias owing to incomplete ascertainment might explain why some previous studies found a seasonal trend in the birth distribution of cystic fibrosis.