Double Heterozygous Autosomal Dominant Hypercholesterolemia: Clinical Characterization of An Underreported Disease

• Published in: Journal of clinical lipidology Vol. 10; no. 6; pp. 1462 - 1469
• Main Authors: Sjouke, B, Defesche, J.C, Hartgers, M.L, Wiegman, A, Roeters van Lennep, J.E, Kastelein, J.J.P, Hovingh, G.K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Apolipoproteins B - genetics; Autosomal dominant hypercholesterolemia; Cardiovascular; Cardiovascular Diseases - etiology; Child; Cholesterol, LDL - blood; Double heterozygous; Familial hypercholesterolemia; Female; Heterozygote; Homozygous; Humans; Hyperlipoproteinemia Type II - complications; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - pathology; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Proprotein Convertase 9 - genetics; Receptors, LDL - genetics; Retrospective Studies; Risk Factors; Young Adult; Phenotype; Autosomal Dominant Hypercholesterolemia; Double Heterozygous; Homozygous; Familial Hypercholesterolemia; Double heterozygous; Familial hypercholesterolemia; Autosomal dominant hypercholesterolemia
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2016.09.003

Abstract Introduction Autosomal dominant hypercholesterolemia (ADH), characterized by high plasma low density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD) risk, is caused by mutations in LDLR , APOB and/or PCSK9. Objective To describe the clinical characteristics of ‘double heterozygous carriers’, with two mutations in two different ADH causing genes i.e. LDLR and APOB or LDLR and PCSK9. Methods Double heterozygotes were identified in the database of the national referral laboratory for DNA diagnostics of inherited dyslipidaemias. We collected the medical data (comprising lipids and CVD events) from double heterozygotes and compared these with data from their heterozygous and unaffected relatives and homozygote/compound heterozygous LDLR mutation carriers, identified in a previously described cohort (n=45). Results A total of 28 double heterozygotes (23 LDLR/APOB and 5 LDLR/PCSK9 mutation carriers) were identified. Off treatment LDL-C levels were significantly higher in double heterozygotes (mean ± SD: 8.4 ± 2.8 mmol/L) compared with 28 heterozygous (5.6 ± 2.2) and 18 unaffected relatives (2.5 ± 1.1; p ≤ 0.01 for all comparisons) and significantly lower compared with homozygous/compound heterozygous LDLR mutation carriers (13.0 ± 5.1; p < 0.001). Conclusions Double heterozygous carriers of mutations in ADH genes express an intermediate phenotype compared with heterozygous and homozygous/compound heterozygous carriers, and might well be misconceived to suffer from a severe form of heterozygous ADH. The molecular identification of double heterozygosity is of relevance from both a screening as well as an educational perspective.