Cystic fibrosis. Part II. New developments in cystic fibrosis--implications for carrier detection and genetic counselling.

Cystic fibrosis (CF) is an autosomal recessive disorder found predominantly in people of European origin. Prenatal diagnosis for this disorder is now possible using the polymerase chain reaction technique to detect the most common CF-causing mutation, delta F508. Case studies of prenatal diagnosis and carrier detection are presented and some of the genetic counselling issues related to these investigations are discussed.

Cystic fibrosis. Part I. Frequency of the delta F508 mutation in South African families with cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disorder among people of European origin. With the localisation of the gene locus to chromosome 7q31 and the identification of closely linked polymorphic markers in 1985, it became possible to offer prenatal testing to couples at risk of having CF children, provided a live affected individual from that family was available for investigation. The CF gene, named CFTR, was cloned and sequenced in 1989 and the most common CF-causing mutation, delta F508, identified. A search for this mutation has been carried out in 81 South African white CF families of European origin. Using the polymerase chain reaction (PCR) technique the frequency of delta F508 was found to be 0.81. This mutation was not found in the 1 negroid and the 1 Indian CF family investigated.

Preventing cystic fibrosis in the RSA.

Prenatal diagnostic testing for cystic fibrosis (CF) in South Africa has been available by microvillar enzyme (MVE) assay since 1984 and by DNA investigation since 1987. The advantages and practical uses of these two procedures are reviewed. Over the period 1984-1989, 59 MVE assays and 13 DNA investigations (1 woman had both done; total number of pregnancies tested 71) were performed for the prenatal diagnosis of CF in high-risk families. Of the 71 pregnancies tested (65 white woman, 4 mixed race and 2 Indian), 18 fetuses were found to be affected: of these, 15 couples chose to have the pregnancies terminated. In 2 fetuses tested the MVE assays were 'equivocal' and the babies were born affected. By using population genetic and demographic data it is estimated that the present rate of prenatal diagnosis and prevention satisfies about one-quarter of the projected and practically achievable annual need. It is also tentatively shown that only about 60% of the projected number of high-risk families are at present on record. It is concluded that more systematic efforts should be directed at carefully guided information and awareness campaigns, in order to draw more CF families into the mainstream of voluntary genetic services. The identification and cloning of the CF gene (in 1989) has made it possible to extend considerably the present strategy of prevention and to include lower-risk and extended CF families in due time.

Study of 30 DNA markers in three southern African populations.

Thirty anonymous DNA markers were investigated in Southern African Caucasoid, Negroid and San populations. Sixteen of these are new markers that were developed in our laboratory; the remainder are closely linked to the cystic fibrosis locus on chromosome 7. Average heterozygosity in the Caucasoid and Negroid populations was calculated at the loci identified by each of the anonymous probes, using two approaches, and was found to be .0020 and .0030 for the Caucasoid population and .0023 and .0025 for the Negroid population. Variation between populations (measured by FST) and between markers was calculated from allele frequency data gathered for all markers in the three populations. Significant differences in allele frequency between the populations were observed for the cystic fibrosis markers MET D, MET H and 7C22, with little or no variation observed in the Negroid and San populations. Mean heterozygosity (D) was found to be considerably lower in San (.250) than in Caucasoid (.373) and Negroid populations (.0320) and possible explanations for this are provided. The smallest genetic distance (60 x 10(-3)) was found between the Negroid and San populations, and the greatest distance between the Caucasoid and San populations (167 x 10(-3)).

Clinical features of superficial spreading melanomas with zones of regression.

To assess the significance of spontaneous regression in superficial spreading melanoma (SSM), 36 patients with clinical signs of regression in their primary tumor were compared to 200 patients with regular SSMs (controls). SSMs with regression were found to have the following, distinctive clinical features, which were significantly different from controls (P less than 0.05): (1) male predominance (69%), (2) preferential localization on the trunk (80.6%), (3) lower tumor thickness (Breslow), (4) clustering in Clark levels II and III, and (5) a larger surface area. The incidence of metastases was lower in patients with regressing SSMs (13.9%) compared to controls (20.5%) although the time until relapse was slightly shorter (20.6 months versus 28.1 months for controls). These prognostic parameters were not significantly different. However, of the patients who died, 2 of 4 with zones of regression had thin melanomas (less than or equal to 1.5 mm), compared to only 1 of 27 without regression zones (P less than 0.05). SSMs with regression therefore have unique clinical features, which may be related to their pathogenesis, and they may have some prognostic significance.