Abstract
BackgroundHypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). However, the spectrum of mutations in the LDLR gene in Sri Lankan patients has not been investigated. The objective of this study was to report the frequency and spectrum of variants in LDLR in a cohort of Sri Lankan patients with FH.MethodsA series of consecutive patients with FH, diagnosed according to Modified Simon Broome criteria or Dutch Lipid Clinic Network criteria at the University Medical Unit, Colombo, were recruited. Clinical data was recorded. DNA was extracted from peripheral blood samples. The LDLR gene was screened for genetic variants by Sanger sequencing.ResultsA total of 27 patients [13 (48%) males, 14 (52%) females; age range 24–73 years] were tested. Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients. In the entire cohort, mean total cholesterol was 356.8 mg/dl (±66.4) and mean LDL-cholesterol was 250.3 mg/dl (±67.7). Sanger sequencing of the 27 patients resulted in the identification of known pathogenic missense mutations in 5 (18.5%) patients. Four were heterozygotes for 1 mutation each. They were c.682G > C in 2 patients, c.1720C > A in 1 patient, and c.1855 T > A in 1 patient. One patient with severe FH phenotypes was a compound heterozygote for one known mutation, c.2289G > T, and another missense variant, c.1670C > G (p.Thr557Ser), with unknown functional impact. This latter variant has not been reported in any other population previously.ConclusionsThe frequency of known mutations in the LDLR gene in this cohort of patients was markedly low compared to frequencies reported in other populations. This highlights the likelihood of a complex, polygenic inheritance of FH in Sri Lankan patients, indicating the need for a comprehensive genetic evaluation that includes the screening for mutations in other genes that cause FH, such as APOB, PCSK9, and LDLRAP1.
Highlights
Hypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality
Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism characterized by elevated low density lipoprotein (LDL) cholesterol in serum, tendon xanthomas and increased risk of premature coronary artery disease (CAD)
Mutations in the genes that encode proteins involved in LDL uptake and catabolism, the LDLreceptor (LDLR), apolipoprotein-B (APOB), LDL receptor adaptor protein (LDLRAP1) and PCSK9 (PCSK9) are known to cause familial hypercholesterolemia (FH), resulting from defective LDL uptake and degradation
Summary
Hypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). Mutations in the genes that encode proteins involved in LDL uptake and catabolism, the LDLreceptor (LDLR), apolipoprotein-B (APOB), LDL receptor adaptor protein (LDLRAP1) and PCSK9 (PCSK9) are known to cause FH, resulting from defective LDL uptake and degradation. This leads to elevations in plasma LDLcholesterol levels, resulting in the hypercholesterolemia phenotype, and manifesting as xanthomas, atherosclerosis, CAD and other cardiovascular diseases. Homozygous and compound heterozygous mutations in LDLRAP1 produce a rare autosomal recessive form of FH [1,2,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
