Generalized thyroid hormone resistance recently was reported to map in a single kindred to the same chromosomal region as the c-erbA beta gene, which codes for a putative thyroid hormone receptor. Restriction fragment length polymorphisms (RFLPs) of c-erbA beta were linked with GTHR in three kindreds with variable neuropsychologic dysfunction; two unrelated kindreds have been reported to possess different single base mutations in the T3 binding domain of c-erbA beta. In order to ascertain if tight linkage with c-erbA beta could be generalized to other families with this syndrome, we performed RFLP analysis in a separate laboratory on an unrelated family with GTHR which lacks the neuropsychologic defects or short stature often associated with GTHR (Kindred WR). RFLPs were identified after Bam Hl and Eco RV digestion of DNA from leukocytes from 14 family members. The Bam Hl RFLPs were 2.8 and 5.3 kb bands, and the Eco RV RFLPs were 1.6 and 3.3 kb bands. These RFLPs cosegregated with the GTHR phenotype and 11 family members were informative when both RFLPs were employed. The logarithm of the odds ratio between GTHR and c-erbA beta was 3.67, and therefore GTHR mapped to the c-erbA beta locus in this kindred. Allelic-specific hybridization with a probe constructed to identify the C to A mutation at nucleotide position 1643 (previously identified in one other kindred) suggested that our family has a different c-erbA beta abnormality. Although GTHR appears to be commonly associated with alterations in the human c-erbA beta gene, different kindreds may inherit different genetic defects.