title: Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family.
abstract: BACKGROUND
  Autosomal dominant hypercholesterolemias (ADHs) are characterised by increased plasma levels of total and LDL cholesterol, predisposing to premature atherosclerosis. ADHs comprise several diseases with undistinguishable phenotype, caused by mutations in different genes: LDLR, APOB and PCSK9. Genetic studies are usually performed in patients with altered cholesterol levels. However, some persons carrying pathogenic mutations are normocholesterolemic and there are no further studies about this subject. We have studied the frequency of families and individuals carrying ADH mutations who do not present the disease in Spanish population.
  
  
  METHODS
  We have analysed genes known to cause ADH by direct sequencing in 24 ADH families (215 members). Functional effect of some LDLR gene mutations was assessed by transfecting cultured cells with plasmids.
  
  
  RESULTS
  Six families with mutations presented 7 mutation carriers who did not show ADH phenotype: 30% of ADH families presented normocholesterolemic individuals, and 7% of carriers of pathogenic mutations did not show ADH phenotype. We have analysed the effect of some of these mutations and they are responsible for impaired LDL receptor function. We have excluded mutations in APOB and PCSK9 genes that could reduce LDLc levels.
  
  
  CONCLUSIONS
  An important percentage of ADH families presented individuals who do not show an ADH phenotype, but who are able to transmit the pathogenic mutation to their offspring. Genetic study of all subjects in ADH families should be performed in order to identify normocholesterolemic carriers that allow the detection of mutations in their descendants and the prevention of the disease consequences.
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas, Barcelona, Spain. a.barbara.garcia@uv.es
authors.forename: Ana-Barbara
authors.initials: AB
authors.lastname: Garcia-Garcia
authors.forename: Carmen
authors.initials: C
authors.lastname: Ivorra
authors.forename: Sergio
authors.initials: S
authors.lastname: Martinez-Hervas
authors.forename: Sebastian
authors.initials: S
authors.lastname: Blesa
authors.forename: M José
authors.initials: MJ
authors.lastname: Fuentes
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Martín-de-Llano
authors.forename: Rafael
authors.initials: R
authors.lastname: Carmena
authors.forename: Jose T
authors.initials: JT
authors.lastname: Real
authors.forename: Felipe Javier
authors.initials: FJ
authors.lastname: Chaves
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D008078:Cholesterol, LDL / Q000235:genetics*; D005192:Family Health; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics; D013030:Spain
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases