Diagnosis of heterozygous familial hypercholesterolemia. DNA analysis complements clinical examination and analysis of serum lipid levels.

Abstract

The concordance of clinical and molecular genetic diagnoses of heterozygous familial hypercholesterolemia (FH) was studied in 65 subjects (10 propositi and 55 first-degree relatives) from 10 families with FH. Nine propositi were carriers of the FH-Helsinki deletion of the low density lipoprotein (LDL) receptor gene, prevalent in the Finnish population, while a new deletion, extending from intron 14 to intron 15 of the LDL receptor gene, was identified in one family. Serum LDL cholesterol levels used in the clinical diagnosis (<5.0 mmol/1, not FH; 5.0-5.9 mmol/l, possible FH; 2:6.0 mmol/1, FH; limits are 1 mmol/1 lower for those <18 years) were derived from an authoritative recommendation. Tendon xanthomas constituted an additional criterion. With the DNA analysis as the reference, 55 (85%) subjects could be correctly classified clinically as FH patients or subjects without FH. The remaining 10 subjects were misclassified or were in the "possible FH" category. When the age-and sex-specific 95th percentile LDL cholesterol levels were used instead of the rigid values for both adults and children, the percentage of correct diagnoses rose to 95%. Common genetic polymorphisms of apolipoproteins E and B did not markedly affect LDL cholesterol levels in FH patients, whereas increasing age and obesity were associated with elevated LDL levels. In conclusion, DNA analysis is a valuable adjunct to the diagnosis of FH that is applicable to families with a known mutation of the LDL receptor gene. If DNA methods are not available, age-and sex-specific LDL levels should be used as an aid in the clinical diagnosis of FH. (Arteriosclerosis and Thrombosis 1992;12:584-592) KEYWORDS • familial hypercholesterolemia • low density lipoprotein receptor gene • apolipoprotein B • apolipoprotein E R ecent developments in the treatment of hyperlipidemias have led to an increasing need for systematic recommendations for the recognition and management of these disorders.1 -2 The diagnosis of familial hypercholesterolemia (FH) has relied on its principal clinical features: elevated serum total and low density lipoprotein (LDL) cholesterol concentrations, the presence of tendon xanthomas and premature coronary heart disease (CHD), and similar findings in a first-degree relative.3 FH is caused by a mutation of the LDL receptor gene, resulting in the defective functioning and/or a diminished number of LDL receptors in the hepatic and other cells, which in turn is accompanied by the slow receptor-mediated catabolism of LDL and the accumulation of LDL in the circulation.3 "

Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo.

“…810 There appear to be no differences in serum lipid levels between patients with these two mutation types. 9 In our recent study 10 on the concordance of clinical and molecular genetic diagnosis of FH we encountered another LDL receptor gene mutation, designated FHEspoo. Preliminary data suggested that the FH-Espoo gene most likely results from deletion of exon 15 of the LDL receptor gene.…”

“…Preliminary data suggested that the FH-Espoo gene most likely results from deletion of exon 15 of the LDL receptor gene. 10 Exon 15 is of special interest in that it encodes the domain with O-linked sugars situated extracellularly between the membrane-spanning region and the epidermal growth factor homology domain of the LDL receptor protein. 1112 Davis et al 13 used oligonucleotide-directed mutagenesis to delete the cDNA segment encoding this receptor domain with clustered serine and threonine residues.…”

“…13 Although the proband with the FHEspoo mutation in our preliminary study was originally identified from a pool of FH patients, two young members of the same family were found to have relatively low serum LDL concentrations. 10 These findings prompted us to characterize this mutation in more detail as well as to clarify whether the associated clinical syndrome would turn out to be different from the classic form of heterozygous FH, exemplified by carriers of the FH-Helsinki mutation. 810…”

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

“…A DNA vs cholesterol diagnostic study of an extended Irish family showed that 15 ± 20% of family members would have been incorrectly diagnosed based on cholesterol testing alone, 24 and in a Finnish study, 10 ± 20% of relatives would have been misdiagnosed. 21 Month-tomonth variability of lipids and lipoproteins and apolipoproteins has also been observed, and in a study of 63 school children, recent infection significantly lowered high density lipoprotein (HDL) whilst LDL-C was shown to be slightly elevated. 25 Thus total cholesterol, LDL-C and triglyceride levels could be falsely high after an acute infection and result in misdiagnosis.…”

“…Screening is simpler in populations where there is a founder gene, such as South Africa 26 and Quebec in Canada, 27 or in populations where there are a limited number of mutations in the majority of FH individuals, such as Iceland 28 and Finland 21 or where there are good traceable family records such as Utah, USA. 29 In heterogeneous populations, a larger number of mutations are found and thus a wider screening approach must be undertaken, as reported in Denmark, 30 Netherlands 31,32 and Italy.…”