Gene probes in diagnosis of familial hypercholesterolemia.

In the United Kingdom, about 5% of patients with familial hypercholesterolemia (FH) have a detectable deletion or rearrangement of part of the LDL-receptor gene, which results in the detection of shorter or abnormally sized fragments of the LDL-receptor gene in a Southern blot hybridization. This gene deletion can be used for following the inheritance of the defective gene and for diagnosis in the families of these individuals. In the families of the remaining patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now 10 common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and, therefore, RFLPs are potentially informative for DNA diagnosis. For a fetus at risk of homozygous FH, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base-pair change causing the defect in the LDL receptor itself creates or destroys a site for a restriction enzyme. Such "mutation-specific" RFLPs could be used for population screening, but, so far, such use has only been reported for the FH mutation common in Lebanon. In the future, it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of FH. These would be appropriate for screening populations or patients with hyperlipidemia. This information may also be useful if different mutations require different therapeutic strategies.