The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi: Tetraploidy is characterized by four complete sets of chromosomes (4n= 92). Although it has been frequently reported in spontaneous abortions, tetraploidy is extremely rare in term pregnancy. Most of late surviving patients are diploid/tetraploid mosaics and present severe mental and physical impairment. Up to date, only five tetraploidies were ascertained in the prenatal stage in amniocytes and/or fetal blood lymphocytes. No one has been reported in chorionic villi probably because tetraploidy is generally considered in this tissue as a false positive result due to confined placental mosaicism (CPM) or placental culture artefacts. We report here on a case of tetraploidy detected in chorionic villi because of fetal cystic hygroma. We discuss the reliability of this diagnosis and propose guidelines in the follow-up of tetraploidies detected after chorionic villus sampling (CVS). Thus a misdiagnosis of this poor condition will be avoided at best and an appropriate genetic counseling will be given to the parents.

In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy.

Prenatal diagnosis for Duchenne muscular dystrophy can usually be performed using DNA analysis. This approach would be impossible when there is only one prior affected male and no identifiable gene deletion. Therefore, in utero fetal thigh muscle biopsy with direct examination of muscle by dystrophin analysis may provide the only means of prenatal diagnosis. We report such a case in which fetal muscle biopsy was able to exclude Duchenne muscular dystrophy. A detailed literature review of the topic is provided.

[Development of an exposure index of air pollution caused by motor vehicles for use in epidemiological studies]. / Elaboration d'un indice d'exposition a la pollution atmospherique d'origine automobile a l'usage des etudes epidemiologiques.

Air pollution due to motor vehicles is a worrying issue, in particular in the urban environment, all the more as a number of pollutants such as benzene and PAH are known to have carcinogenic effects. Epidemiological studies seem to be required, so a cumulated score of exposure must be developed. A correlation with pathology should be investigated. The calculation of an index of exposure to motor vehicle-related pollution requires a good assessment of pollutant emissions and a precise knowledge of pollutant transfer mechanisms by advection and spreading in built-up areas. In this study, it is proposed to use current theoretical and experimental knowledge to develop a calculation algorithm for this index. The following issues will be addressed in the presentation: an analysis of epidemiological requirements and of constraints of data acquisition using questionnaire surveys; a model for assessing, for each residential area, the average annual concentration of gaseous pollutants from motor vehicles. It will consider the environment geometry, traffic emissions and wind distributions. The model CALINE3 is used for open areas near roads and highways and the Danish model OSPM is introduced for street canyon environments.

Direct fetal chromosome studies from chorionic villi.

An easy and reproducible technique for direct fetal chromosome analysis after chorionic biopsy is described. Very high colchicine concentration and rehydratation of the fixed villi are the two original points of this method.

[Determination of fetal karyotype in the first trimester of pregnancy by direct examination of chorionic villi]. / Détermination du caryotype foetal au premier trimestre de la grossesse par examen direct des villosités choriales.

Chorionic biopsy during the first trimester of pregnancy allows fast and precise study of fetal karyotype. Considering the results of our ten prenatal diagnoses, we discuss the advantages and the risks of this method.