Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families

Thilo Dörk*, Thomas Neumann, Ulrich Wulbrand, Brigitte Wulf, Nanette Kälin, Günter Maa, Michael Krawczak, Hervé Guillermit, Claude Ferec, Glenn Horn, Katherine Klinger, Bat Sheva Kerem, Julian Zielenski, Lap Chee Tsui, Burkhard Tümmler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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In order to facilitate the screening for the less common mutations in the cystic fibrosis (CF) gene viz., the CF transmembrane conductance regulator gene (CFTR), marker haplotypes were determined for German nonCF (N) and CF chromosomes by polymerase chain reaction analysis of four polymorphisms upstream of the CF gene (XV-2c, KM.19, MP6-D9, J44) and six intragenic polymorphisms (GATT, TUB9, M470V, T854T, TUB18, TUB20) that span the CFTR gene from exon 6 through exon 21. Novel informative sequence variants of CFTR were detected in front of exons 10 (1525-61 A or G), 19 (3601-65 C or A), and 21 (4006-200 A or G). The CF locus exhibits strong long-range marker-marker linkage disequilibrium with breakpoints of recombination between XV-2c and KM.19, and between exons 10 and 19 of CFTR. Marker alleles of GATT-TUB9 and TUB18-TUB20 were found to be in absolute linkage disequilibrium. Four major haplotypes encompass more than 90% of German N and CF chromosomes. Fifteen CFTR mutations detected on 421 out of 500 CF chromosomes were each identified on one of these four predominant 7-marker haplotypes. Whereas all analysed ΔF508 chromosomes carried the same KM.19-D9-J44-GATT-TUB9-M470V-T854T haplotype, another frequent mutation in Germany, R553X, was identified on two different major haplotypes. Hence, a priori haplotyping cannot exclude a particular CF mutation, but in combination with population genetic data, enables mutations to be ranked by decreasing probability.

Original languageAmerican English
Pages (from-to)417-425
Number of pages9
JournalHuman Genetics
Issue number4
StatePublished - Feb 1992


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