Cascade genetic screening for familial hypercholesterolemia

   Familial hypercholesterolemia (FH) is one of the most common congenital metabolic disorders. Cascade genetic screening used for diagnostic of patients with FH. Aim of study is to explore the awareness of FH patients of the problem of familial hypercholesterolemia and conduct a pilot study of patients with FH using the principle of a cascade genetic screening. The study was performed in patients with a clinical diagnosis of “definite” FH. The study was approved ethics committee. Target was selected for high-throughput sequencing (GS Junior, Roche). Participation in the survey was voluntary and anonymous. An analysis of the responses to the questions provided data on the lack of awareness of patients with the FH about the problem. Certain mutations in this study and LDLR gene polymorphisms confirmed genetic heterogeneity of the spectrum of structural modifications of LDL receptor gene in patients with FH.

1. Rader D. J., Cohen J., Hobbs H. H. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment // J. Clin. Invest. 2003. Vol. 111. P. 1795–1803.

2. De Castro-Oros I., Pocoví M., Civeira F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations // Appl. Clin. Genet. 2010. Vol. 3. P. 53–64.

3. Vella A., Pineda A. A., O’Brien T. Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia // Mayo Clin. Proc. 2001. Vol. 76. P. 1039–1046.

4. Thompsen J., Thompson P. D. A systematic review of LDL apheresis in the treatment of cardiovascular disease // Atherosclerosis. 2006. Vol. 189. P. 31–38.

5. DeMott K., Nherera L., Shaw E. J., Minhas R., Humphries S. E., Kathoria M., Ritchie G., Nunes V., Davies D., Lee P., McDowell I., Neil A., Qureshi N., Rowlands P., Seed M., Stracey H., Thorogood M., Watson M. Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners, 2008.

6. Leren T. P. Cascade genetic screening for familial hypercholesterolemia // Clin. Genet. 2004. Vol. 66. P. 483–487.

7. Leren T. P., Finborud T. H., Manshaus T. E., Ose L., Berge K. E. Diagnosis of Familial Hypercholesterolemia in General Practice Using Clinical Diagnostic Criteria or Genetic Testing as Part of Cascade Genetic Screening // Comm. Genet. 2008. Vol. 11. P. 26–35.

8. Nordestgaard B. G., Chapman M. J., Humphries S. E., Ginsberg H. N., Masana L., Descamps O. S., Wiklund O., Hegele R. A., Raal F. J., Defesche J. C., Wiegman A., Santos R. D., Watts G. F., Parhofer K. G., Hovingh G. K., Kovanen P. T., Boileau C., Averna M., Borén J., Bruckert E., Catapano A. L., Kuivenhoven J. A., Pajukanta P., Ray K., Stalenhoef A., Stroes E., Taskinen M. R., Tybjærg-Hansen A. Forthe European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease // Eur. Heart J. 2013. Vol. 34. P. 3478–3490.

9. Minhas R., Humphries S. E., Qureshi N. Neil HAW. On behalf of the Nice Guideline Development Group. Controversies in familial hypercholesterolaemia: recommendations of the NICE Guideline Development Group for the identification and management of familial hypercholesterolaemia // Heart. 2009. Vol. 95. P. 584–587.

10. Martin A. C., Coakley J., Forbes D. A., Sullivan D. R., Watts G. F. J. Familial hypercholesterolaemia in children and adolescents: a new paediatric model of care // Paediatr. Child. Health. 2013. Apr. Vol. 9 (4). P. E263–E272.

11. Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygousfamilialhypercholesterolaemia: implications for clinical management // Atherosclerosis. 1999. Vol. 142. P. 105–112.

12. World Health Organization. Familial hypercholesterolaemia. Report of a second WHO consultation. Geneva: World Health Organization, 1999.

13. Смит К. Анализ генома / К. Смит, С. Калко, Ч. Кантор; под ред. К. Дейвиса, пер. с англ. – М.: Мир, 1990. – С. 58–94.

14. Gent J., Braakman I. Low-density lipoprotein receptor structure and folding // Cell. Mol. Life Sci. 2004. Vol. 61 (19–20). P. 2461–2470.

15. Magana Torres, Mora-Hernandez, Vazquez Cardenas, Gonzalez Jaimes. Homozygous familial hypercholesterolemia: the c.1055G>A mutation in the LDLR gene and clinical heterogeneity // J. Clin. Lipidol. 2014. Vol. 8 (5). P. 525–527.

16. Feussner G., Dobmeyer J., Nissen H., Hansen T. S. Unusual Xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia // Am. J. Med. Genet. 1996. Vol. 65. P. 149–154.

17. Lаmsа R., Helisalmi S., Herukka S. K., Tapiola T., Pirttilа T., Vepsаlаinen S., Hiltunen M., Soininen H. Genetic study evaluating LDLR polymorphisms and Alzheimer’s disease // Neurobiol. Aging. 2008. Jun. Vol. 29 (6). P. 848–855.

18. Yan H. C., Wang W., Dou C. W., Tian F. M., Qi S. T. Relationships of LDLR genetic polymorphisms with cerebral infarction: a meta-analysis // Mol. Biol. Rep. 2014. Jul. Vol. 41 (7). P. 4425–4434.

19. Boes E. l., Coassin S., Kollerits B., Heid I. M., Kronenberg F. Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: a systematic in-depth review // Exp. Gerontol. 2009. Mar. Vol. 44 (3). P. 136–160.

20. Lee J. D., Hsiao K. M., Wang T. C., Lee T. H., Kuo Y. W., Huang Y. C., Hsu H. L., Lin Y. H., Wu C. Y., Huang Y. C., Lee M., Yang H. T., Hsu C. Y., Pan Y. T. Mutual effect of rs688 and rs5925 in regulating low-density lipoprotein receptor splicing // DNA Cell Biol. 2014. Dec. Vol. 33 (12). P. 869–875.

21. Adzhubei I. A., Schmidt S., Peshkin L., Ramensky V. E., Gerasimova A., Bork P., Kondrashov A. S., Sunyaev S. R. A method and server for predicting damaging missense mutations // Nat. Methods. 2010. Apr. Vol. 7 (4). P. 248–249.

22. Мандельштам М. Ю. Диагностика семейной гиперхолестеринемии в России: достижения и проблемы / М. Ю. Мандельштам [и др.] // Молекулярно-биологические технологии в медицинской практике. – Новосибирск: Альфа-Виста, 2004. – С. 9–23.

23. Heath K. E., Gahan M., Whittall R. A., Humphries S. E. Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis // Atherosclerosis. 2001. Vol. 154. P. 243–246.

24. Мандельштам М. Ю. Что дало изучение семейной гиперхолестеринемии для понимания генетики дислепидемий? / М. Ю. Мандельштам // Мед. генетика. – 2003. – Т. 2, № 12. – С. 509–519.

25. Zakharova F. M., Damgaard D., Mandelshtam M. Y. et al. Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia // BMC Med. Genetics. 2005. Vol. 6. P. 6.

26. Комарова Т. Ю. «Финские» мутации в гене рецептора ЛПНП — редкая причина семейной гиперхолестеринемии в Санкт-Петербурге и Петрозаводске / Т. Ю. Комарова [и др.] // Бюл. эксперим. биологии и медицины. – 2013. – Т. 155, № 3. – C. 359–362.

27. Воевода М. И. Популяционное исследование спектра мутаций гена рецептора липопротеинов низкой плотности в российской популяции / М. И. Воевода [и др.] // Генетика. – 2008. – № 10. – С. 1374–1378.

28. Galema-Boers J. M. H., Versmissen J., Roeters van Lennep H. W. O., Dusault-Wijkstra J. E., Williams M., Roeters van Lennep J. E. Cascade screening of Familial Hypercholesterolemia must go on // Atherosclerosis. 2015. Oct. Vol. 242 (2). P. 415–217.

29. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation // Int. J. Cardiol. 2014. Vol. 171. P. 309–325.