title: Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic.
abstract: OBJECTIVE
  To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate.
  
  
  METHODS
  289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication.
  
  
  RESULTS
  An FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 × 10(-5)) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 × 10(-6) respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68).
  
  
  CONCLUSIONS
  In this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, Rayne Building University College London, London WC1E 6JF, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.forename: Ros A
authors.initials: RA
authors.lastname: Whittall
authors.forename: Amy
authors.initials: A
authors.lastname: Kiley
authors.forename: Louisa K
authors.initials: LK
authors.lastname: Steel
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Ebele
authors.initials: E
authors.lastname: Badmus
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Leigh
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: H Andrew W
authors.initials: HA
authors.lastname: Neil
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005820:Genetic Testing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010044:Outpatient Clinics, Hospital; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D006113:United Kingdom
chemical_list: D001055:Apolipoproteins B; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases