Barbara Sjouke1, Joep C Defesche2, Merel L Hartgers3, Albert Wiegman4, Jeanine E Roeters van Lennep5, John J Kastelein3, G Kees Hovingh3. 1. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: b.sjouke@amc.uva.nl. 2. Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 3. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 4. Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands. 5. Department of Internal Medicine, Erasmus Medical Centre, Erasmus University of Rotterdam, Rotterdam, The Netherlands.
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 2 mutations in 2 different ADH causing genes, that is, 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 dyslipidemias. 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 ≤ .01 for all comparisons) and significantly lower compared with homozygous/compound heterozygous LDLR mutation carriers (13.0 ± 5.1; P < .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 and an educational perspective. Copyright Â
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 2 mutations in 2 different ADH causing genes, that is, 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 dyslipidemias. 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 5LDLR/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 ≤ .01 for all comparisons) and significantly lower compared with homozygous/compound heterozygous LDLR mutation carriers (13.0 ± 5.1; P < .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 and an educational perspective. Copyright Â