Abstract We have analysed 1173 cystic fibrosis (CF) chromosomes from Switzerland for eight mutations in the CF transmembrane conductance regulator (CFTR) gene. This permitted the identification of 88.5% of all mutations present. A novel insertion mutation in exon 20 of the CFTR gene, 3905insT, was discovered. This mutation ac- counted for 4.8% of CFTR gene mutations in Switzerland and has since been identified in other populations of prob- able Swiss descent. It is associated with a highly variable clinical phenotype but always with pancreatic insuffi- ciency. Haplotype analysis with three intragenic mi- crosatellites in the CFTR gene showed that the mutation is associated with a haplotype rarely identified on other CFTR alleles and, therefore, that the frequency of the mu- tation in Switzerland is explained by a founder effect of a relatively recent mutation event. Introduction Cystic fibrosis (CF) is the most common lethal autosomal recessive disease of the Caucasian population. Over 500 pathogenic mutations have been identified in the CF trans- membrane conductance regulator (CFTR) gene, which en- codes a chloride channel located in the apical membranes of the epithelial cell (reviewed in The Cystic Fibrosis Ge- netic Analysis Consortium 1994; Welsh et al. 1995; Es- tivill 1996). An analysis of the distribution of different mutations in a population is a prerequisite for risk calcu- lation for couples with one identified carrier. In addition, the diversity of CFTR mutations has raised questions re- garding the feasibility of CF carrier screening in heteroge- neous populations. In Switzerland, the frequency of CF has been estimated to be 1 in 2000, implying a carrier fre- quency of between 1 in 20 and 1 in 25 (Kraemer et al. 1977). The molecular biological laboratories of the five Swiss University Centres for medical genetics have of- fered analysis of eight relatively common mutations of the CFTR gene during the last 6 years as a tool for differential diagnosis and for genetic counselling of families with a history of CF. From haplotype analysis using restriction fragment length polymorphisms, the existence of a muta- tion responsible for a significant proportion of the non- ∆F508 mutations was predicted (Liechti-Gallati et al. 1991). Haplotype analysis, both in general and of the CFTR gene in particular, has been refined during recent years by the use of highly polymorphic microsatellite polymorphisms. Recently, these intragenic polymor- phisms have been used to describe the evolutionary and population history of a number of CF mutations, most no- tably of ∆F508 (Morral and Estivill 1992; Morral et al. 1994, 1996). We describe here the results of mutation analysis in 606 CF families in Switzerland, who were tested for eight different mutations, including the newly identified 3905insT mutation, which was found to be the second most common CF mutation in our sample. Using three in- tragenic microsatellites, strong evidence was found for a recent and unique origin of the 3905insT mutation. Martin Hergersberg · Jaya Balakrishnan · Thomas Bettecken · Francoise Chevalier-Porst · Christian Brägger · René Burger · Inge Einschenk · Sabina Liechti-Gallati · Michael Morris · Daniel Schorderet · Francine Thonney · Hans Moser · Naseem Malik A new mutation, 3905insT, accounts for 4.8% of 1173 CF chromosomes in Switzerland and causes a severe phenotype Hum Genet (1997) 100 : 220–223 © Springer-Verlag 1997 Received: 17 February 1997 / Accepted: 26 March 1977 ORIGINAL INVESTIGATION M. Hergersberg () · J. Balakrishnan · I. Einschenk Institut für Medizinische Genetik, Universität Zürich, Rämistrasse 74, CH-8001 Zurich, Switzerland Tel.: +411 257 25 35; Fax: +411 262 04 70; e-mail hergie@medgen.unizh.ch T. Bettecken · S. Liechti-Gallati · H. Moser Universitäts-Kinderklinik, Bern, Switzerland F. Chevalier-Porst Hôpital Debrousse, Lyon, France C. Brägger · R. Burger Universitäts-Kinderklinik, Zurich, Switzerland M. Morris Division de Génétique Médicale, Gèneve, Switzerland D. Schorderet · F. Thonney Division Autonome de Génétique Médicale, Lausanne, Switzerland N. Malik Abteilung für Medizinische Genetik, Universitätskinderklinik, Basel, Switzerland