Polygenic Causes of Hypercholesterolaemia Minimize Effectiveness of Cascade Testing
Familial hypercholesterolaemia can be caused by an accumulation of common small-effect alleles instead of a dominant monogenic mutation, which could compromise the efficiency of cascade testing, according to a study published online Feb. 22 in Lancet. The authors suggest such cascade testing should be restricted to patients positive for one of three known dominant autosomal mutations, rather than those with polygenic causes of hypercholesterolaemia. Patients with familial hypercholesterolaemia typically have significantly escalated low-density lipoprotein cholesterol (LDL-C) and a five to eight times increased risk of early coronary heart disease. However, there is no single accepted criterion for the diagnosis of the condition. Clinical diagnosis misses significant numbers of patients, and genetic testing is complicated by the polygenetic nature of the condition. A strategy of cascade testing of first-degree relatives of an index patient with DNA-confirmed hypercholesterolaemia is employed in several European nations and New Zealand, but the effectiveness of this strategy may be compromised with these findings of polygenic causes of the condition. “The inclusion of probands with polygenic rather than monogenic cause of hypercholesterolaemia would reduce the efficiency of any cascade screening program, since much less than the expected 50 percent of first-degree relatives would be affected,” write the […]
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