Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene S. Lind a, * ,1 , E. Rystedt b , M. Eriksson c , O. Wiklund d , B. Angelin c , G. Eggertsen b a Department of Medical Laboratory Sciences and Technology, Centre for Inherited Metabolic Diseases, Karolinska Institute at Huddinge University Hospital, S-141 86 Stockholm, Sweden b Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institute at Huddinge University Hospital, S- 141 86 Stockholm, Sweden c Department of Medicine and Molecular Nutrition Unit, Center for Metabolism and Endocrinology, Karolinska Institute at Huddinge University Hospital, S-141 86 Stockholm, Sweden d Department of Medicine, Wallenberg Laboratory, Sahlgren’s Hospital, Go¨teborg, Sweden Received 20 July 2001; received in revised form 20 December 2001; accepted 25 January 2002 Abstract Familial hypercholesterolemia (FH) is an autosomal codominant disease, caused by mutations in the LDL receptor gene. To characterize the distribution of genetic aberrations in Swedish FH-patients fulfilling the clinical criteria of FH, we have investigated 150 unrelated Swedish patients for mutations in the LDL receptor gene and for the most common mutation causing familial ligand defective apo B-100 (FDB). Of the patients, 77 were recruited from Huddinge University Hospital in Stockholm and 73 from Sahlgren’s University Hospital in Go¨ teborg. Screening was carried out using SSCP and Southern blotting techniques, combined with DNA sequence analysis. In total, mutations regarded as cause for disease were identified in 55 patients (37%), representing 32 different types of mutations. In the LDL receptor gene we detected four nonsense mutations, 13 missense mutations, seven splice junction mutations, and four major rearrangements. In addition, two small deletions were identified and one base exchange in the promoter region. The most common mutation (apo B3500) causing FDB was found in three patients. The most frequent mutation was FH-Helsinki, reflecting the admixture of Finnish immigrants. We further identified 15 point mutations which were not considered to affect the function of the gene, and thus were regarded as polymorphic changes. This multitude of mutations reflects a heterogeneous genetic background in our series of Swedish FH-patients and differs from the situation in the other Scandinavian countries. Future studies should aim at characterizing the importance of other genes for the development of the FH phenotype. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Familial hypercholesterolemia; LDL receptor gene mutations; Apo B-100 1. Introduction Familial hypercholesterolemia (FH) is an autosomal codominant disease, which is characterized by hyperch- olesterolemia, tendon xanthomas and premature ather- osclerosis. The underlying cause of FH is mutations in the LDL receptor gene (for a review see Ref. [1]) or in the apolipoprotein (apo) B gene, leading to impaired receptor function and a high level of LDL-cholesterol in plasma. In Western Europe, the frequency of hetero- zygous FH is estimated at approximately 1/500 [1], making it one of the most common metabolic disorders. As hypercholesterolemia may be caused by several mechanisms, genetic testing may be the most accurate way for diagnosing FH [2]. Early diagnosis and treat- ment are crucial for the patient [1,3], since progression of cardiovascular complications can be prevented [4]. * Corresponding author. Tel.: /46-8-5858-2793; fax: /46-8-5858- 1260. E-mail address: suzanne.lind@cmms.hs.sll.se (S. Lind). 1 S. Lind and E. Rystedt contributed equally. Atherosclerosis 163 (2002) 399 /407 www.elsevier.com/locate/atherosclerosis 0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(02)00038-2