Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.

Tuesday, 4 December, 2012
  • Rosemary E J Clarke ,
  • Soundrie T Padayachee,
  • Rebecca Preston,
  • Zofia McMahon,
  • Mitchell Gordon,
  • Colin Graham,
  • Martin A Crook,
  • Professor Anthony S. Wierzbicki


Objective:- To determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH).

Design:- A retrospective study of genotyped index patients with Simon Broome (SB) FH.

Setting:- University teaching hospital.

Patients:- 204 patients aged 55±14 years; 36% had tendon xanthoma (TX), 21% had coronary heart disease (CHD), low-density lipoprotein cholesterol (LDL-C) was 6.20±2.24 mmol/l and 55% had genetic FH.

Interventions:- The effects of different staging systems (SB vs Dutch criteria), presence of TX, use of LDL-C level, personal history of CHD and imaging evidence of atheroma by carotid intima-media thickness or coronary artery calcium score to identify genetic FH was explored.

Outcome measures:- Changes in C-statistic and net reclassification index (NRI).

Results:- SB criteria gave a C-statistic of 0.64 comprising C=0.65 in TX(+) and C=0.5 in TX(−) patients. Genetic FH was present in 75% of TX(+) compared with 44% in TX(−) patients. The Dutch criteria gave C=0.72. Addition of imaging criteria to prior CHD raised C=0.64 to C=0.65 in all patients with a NRI of 19% (p=0.06). In TX(−) patients imaging raised C=0.50 to C=0.65 with a NRI of 0.38 (p=0.001) and a weighted comparison index of 0.28, implying the detection of 14 more FH cases per thousand.

Conclusions:- Patients with tendon xanthoma (definite FH) should be genotyped. In patients with possible FH, the presence of a personal history of CHD or imaging evidence of increased atheroma offers the best method of identifying index patients likely to have.

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Published: 2013 Feb;99(3):175-80. doi: 10.1136/heartjnl-2012-302917. Epub 2012 Dec 4.