NOVEL MUTATIONS AND POLYMORPHISMS IN THE FANCONI-ANEMIA GROUP C GENE

Fanconi anemia IFA) is an autosomal recessive disorder associated with hypersensitivity to DNA cross linking agents and bone marrow failure, At least four complementation groups have been defined, and the FA gr oup C gene (FAC) has been cloned. We have screened 76 unrelated FA pat ients of diverse ethnic and geographic origins and from unknown comple mentation groups for mutations in the FAC gene either by chemical clea vage mismatch analysis or by single-strand conformational polymorphism (SSCP). Five mutations were detected in four patients (5.3%), includi ng two novel mutations (W22X and L496R). Nine polymorphisms were detec ted, seven of which have not been described previously (663A-->G, L190 F, IVS6+30C-->T, I312V, V449M, Q465R, and 1974G-->A). Six of the nine polymorphisms occurred in patients or controls from the Tswana or Soth o chiefdoms of South Africa and were not found in 50 unrelated Europea n controls. Restriction site assays were established for all 8 pathoge nic mutations identified in the FAC gene to date and used to screen a total of 94 unrelated FA patients. This identified only one other grou p C patient, who was homozygous for the mutation 1VS4 + 4A-->T. This s tudy indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the s election of FA patients for FAC mutation screening are proposed. (C) 1 996 Wiley-Liss, Inc.