Subspecialty Clinics: Medical Genetics Carrier Identification of Cystic Fibrosis by Recombinant DNA Techniques D. BRIAN DAWSON, Ph.D.,* LAURA A. CUMMINS, B.S., Molecular Genetics Laboratory, Division of Laboratory Medicine; DANIEL J. SCHAID, Ph.D., Section of Biostatistics, Department of Health Sciences Research; VIRGINIA V. MICHELS, M.D., HYMIE GORDON, M.D., Department of Medical Genetics; EDWARD J. O'CONNELL, M.D., Department of Pediatrics; STEPHEN N. THIBODEAU, Ph.D., Molecular Genetics Laboratory, Division of Laboratory Medicine As a result of recent advances in molecular genetics, carrier testing for cystic fibrosis (CF) is now available as a clinical assay in a limited number of laboratories. Because neither the gene nor the mutation for this disorder has yet been defined, the analysis relies on an indirect approach that uses DNA sequence polymorphisms and linkage analysis. With use of this general approach, several family members, in addition to those persons seeking carrier information, must be tested. Currently, more than 97% of families are "fully informative" when these markers are used in a linkage analysis; thus, the carrier status of most persons who have a relative with CF can be determined. Recently, strong linkage disequilibrium has been shown between two polymorphic loci (defined by the DNA probes KM. 19 and XV-2c) and the CF locus. Because of this important finding, haplotype testing can be used in many clinical settings, such as for families in which a DNA sample is not available from the affected person or for those families in which one spouse has no family history of CF and the other is either affected or is at a high risk of carrying the CF mutation. Overall, the application of recombinant DNA techniques has greatly enhanced the ability to determine, with a high level of accuracy, the carrier status of those persons at risk for inheriting the CF mutation. Cystic fibrosis (CF) is a common autosomal re- cessive disorder with an estimated carrier fre- quency of 1 in 25 in a Caucasian population of northern European ancestry. Thus, almost 1 of every 2,500 newborns is affected with this dis- order. The clinical features of the disease can include meconium ileus, pancreatic dysfunction, recurrent pulmonary infections, obstructive pul- monary disease, sinus infections, nasal polyps, ""Current address: University of Texas/Southwestern Medical Center, Dallas, Texas. Address reprint requests to Dr. S. N. Thibodeau, Molecular Genetics Laboratory, Mayo Clinic, Rochester, MN 55905. and sterility in male patients. An additional char- acteristic feature of these patients is the presence of increased sweat electrolytes. The high salt content of sweat has led to research studies that have shown decreased permeability of chloride ions in sweat ducts and in respiratory epithelial cells, which prevents reabsorption of the salt. Evidence is mounting for an intracellular defect that involves the alteration of a regulatory pro- tein distal to the site of formation of cyclic adeno- sine monophosphate, which affects the chloride ion channel. 1 Currently, the diagnosis of CF is based pri- marily on its clinical features and on a positive result of a sweat test (pilocarpine iontophoresis). Mayo Clin Proc 64:325-334,1989 325