Two hundred thirty-four unrelated heterozygotes for familial hypercholesterolemia (FH) were screened to detect major rearrangements in the low-density-lipoprotein (LDL) receptor gene. Total genomic DNA was analyzed by Southern blot hybridization to probes encompassing exons 1-18 of the LDL receptor gene. Six different mutations were detected and characterized by the use of exon-specific probes and detailed restriction mapping. Each mutation is unique and suggests that molecular heterogeneity underlies the molecular pathology of FH. There appear to be preferential sites within the LDL receptor gene for major rearrangements resulting in deletions.