vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-38vavilov-3366Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSАнализ спектра мутаций гена рецептора низкой плотности (LDLR) при семейной гиперхолестеринемии в РоссииAnalysis of the low density lipoprotein receptor gene (LDLR) mutation spectrum in Russian familial hypercholesterolemiahttps://orcid.org/0000-0002-9707-262XВасильевВ. Б.VasilyevV. B.

Санкт-Петербург

St. Petersburg

vadim@biokemis.ruhttps://orcid.org/0000-0002-9558-3979ЗахароваФ. М.ZakharovaF. M.

Санкт-Петербург

St. Petersburg

https://orcid.org/0000-0002-9480-1073БогословскаяТ. Ю.BogoslovskayaT. Yu.

Санкт-Петербург

St. Petersburg

https://orcid.org/0000-0002-7135-3239МандельштамМ. Ю.MandelshtamM. Yu.

Санкт-Петербург

St. Petersburg

Институт экспериментальной медициныРоссияInstitute of Experimental MedicineRussian Federation202204062022263319326Copyright © Васильев В.Б., Захарова Ф.М., Богословская Т.Ю., Мандельштам М.Ю., 20222022Васильев В.Б., Захарова Ф.М., Богословская Т.Ю., Мандельштам М.Ю.Vasilyev V.B., Zakharova F.M., Bogoslovskaya T.Y., Mandelshtam M.Y.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3366

Семейная гиперхолестеринемия – распространенное во всем мире наследственное заболевание человека, при котором чаще всего дефекты обнаруживаются в гене рецептора липопротеинов низкой плотности (LDLR). Цель работы – систематизировать знания о мутациях гена LDLR в России. Проведен анализ литературы по предмету исследования, составлены сводные таблицы, показывающие встречаемость мутаций в отдельных регионах, и определены часто встречающиеся мутации. Более трети (80 из 203, т. е. 39.4 %) патогенных или вероятно патогенных мутаций представлены вариантами, специфичными для России и не встречающимися в других странах. Наибольшее количество вариантов охарактеризовано в крупных городах: Москве (130 патогенных мутаций), Санкт-Петербурге (50), Новосибирске (34) и Петрозаводске (19), тогда как регионы охарактеризованы гораздо хуже. Подавляющее число патогенных мутаций (142 из 203, или 70 %) найдено в единичных семьях, и только 61 вид мутаций встречался в двух или в нескольких родословных. Лишь 5 видов мутаций были найдены не менее чем в 10 семьях. Как и везде в мире, в России в гене LDLR преобладают миссенс-мутации, но особенным национальным своеобразием характеризуются мутации типа сдвига рамки считывания: из 27 найденных вариантов 19 (70 %) специфичны для России. Наивысшее число мутаций в гене LDLR в российской популяции обнаружено в четвертом и девятом экзонах. Это определяется тем, что четвертый и девятый экзоны являются самыми протяженными в гене и кодируют функционально важные участки белка, что обусловливает повышенную плотность патогенных мутаций в расчете на один нуклеотид длины именно в этих экзонах. Российская популяция имеет наибольшее число совпадающих мутаций с популяциями Польши, Чешской Республики, Нидерландов и Италии. Внедрение методов таргетного секвенирования существенно ускорило характеристику мутационного спектра при семейной гиперхолестеринемии, но из-за отсутствия систематических исследований в регионах большинство видов мутаций в России, вероятнее всего, еще не описано.

Familial hypercholesterolemia (FH) is a very common human hereditary disease in Russia and in the whole world with most of mutations localized in the gene coding for the low density lipoprotein receptor (LDLR). The object of this review is to systematize the knowledge about LDLR mutations in Russia. With this aim we analyzed all available literature on the subject and tabulated the data. More than 1/3 (80 out of 203, i. e. 39.4 %) of all mutations reported from Russia were not described in other populations. To date, most LDLR gene mutations have been characterized in large cities: Moscow (130 entries), Saint Petersburg (50 entries), Novosibirsk (34 mutations) and Petrozavodsk (19 mutations). Other regions are poorly studied. The majority of pathogenic mutations (142 out of 203 reported here or 70 %) were revealed in single pedigrees; 61 variants of mutations were described in two or more genealogies; only 5 mutations were found in 10 or more families. As everywhere, missense mutations prevail among all types of nucleotide substitutions in LDLR, but the highest national specificity is imparted by frameshift mutations: out of 27 variants reported, 19 (or 70 %) are specific for Russia. The most abundant in mutations are exons 4 and 9 of the gene due to their largest size and higher occurrence of mutations in them. Poland, the Czech Republic, Italy and the Netherlands share the highest number of mutations with the Russian population. Target sequencing significantly accelerates the characterization of mutation spectra in FH, but due to the absence of systematic investigations in the regions, one may suggest that most of LDLR mutations in the Russian population have not been described yet.

семейная гиперхолестеринемиярецептор липопротеинов низкой плотностимутацииfamilial hypercholesterolemialow density lipoprotein receptor genemutationsReferencesAverkova A.O., Brazhnik V.A., Speshilov G.I., Rogozhina A.A., Koroleva O.S., Zubova E.A., Galyavich A.S., Tereshenko S.N., Boyeva O.I., Zateyshchikov D.A. Targeted sequencing in patients with clinically diagnosed hereditary lipid metabolism disorder and acute coronary syndrome. Bulletin of Russian State Medical University. 2018;5:80-86. DOI 10.24075/brsmu.2018.061.Averkova A.O., Brazhnik V.A., Speshilov G.I., Rogozhina A.A., Koroleva O.S., Zubova E.A., Galyavich A.S., Tereshenko S.N., Boyeva O.I., Zateyshchikov D.A. Targeted sequencing in patients with clinically diagnosed hereditary lipid metabolism disorder and acute coronary syndrome. Bulletin of Russian State Medical University. 2018;5:80-86. DOI 10.24075/brsmu.2018.061.Benn M., Watts C.F., Tybjaerg-Hansen A., Nordestgaard B.G. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication. J. Clin. Endocrinol. Metab. 2012;97(11):3956-3964. DOI 10.1210/jc.2012-1563.Benn M., Watts C.F., Tybjaerg-Hansen A., Nordestgaard B.G. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication. J. Clin. Endocrinol. Metab. 2012;97(11):3956-3964. DOI 10.1210/jc.2012-1563.Berberich A.J., Hegele R.A. The complex molecular genetics of familial hypercholesterolaemia. Nat. Rev. Cardiol. 2019;16(1):9-20. DOI 10.1038/s41569-018-0052-6.Berberich A.J., Hegele R.A. The complex molecular genetics of familial hypercholesterolaemia. Nat. Rev. Cardiol. 2019;16(1):9-20. DOI 10.1038/s41569-018-0052-6.Bertolini S., Pisciotta L., Rabacchi C., Cefalù A.B., Noto D., Fasano T., Signori A., Fresa R., Averna M., Calandra S. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013;227(2):342-348. DOI 10.1016/j.atherosclerosis.2013.01.007.Bertolini S., Pisciotta L., Rabacchi C., Cefalù A.B., Noto D., Fasano T., Signori A., Fresa R., Averna M., Calandra S. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013;227(2):342-348. DOI 10.1016/j.atherosclerosis.2013.01.007.Chakir Kh., Skobeleva N.A., Shevtsov S.P., Konstantinov V.O., Denisenko A.D., Schwartz E.I. Two novel slavic point mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg, Russia. Mol. Genet. Metab. 1998a;63(1):31-34. DOI 10.1006/mgme.1997.2614.Chakir Kh., Skobeleva N.A., Shevtsov S.P., Konstantinov V.O., Denisenko A.D., Schwartz E.I. Two novel slavic point mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg, Russia. Mol. Genet. Metab. 1998a;63(1):31-34. DOI 10.1006/mgme.1997.2614.Chakir K., Mandelshtam M.Ju., Shevtsov S.P., Golubkov V.I., Skobeleva N.A., Shur Yu.A., Zakharova F.M., Lipovetskyi B.M., Konstantinov V.O., Denisenko A.D., Gaitskhoki V.S., Schwartz E.I. Two novel low-density lipoprotein receptor gene mutations (E397X and 347delGCC) in St. Petersburg familial hypercholesterolemia. Mol. Genet. Metab. 1998b;65(4):311-314. DOI 10.1006/mgme.1998.2762.Chakir K., Mandelshtam M.Ju., Shevtsov S.P., Golubkov V.I., Skobeleva N.A., Shur Yu.A., Zakharova F.M., Lipovetskyi B.M., Konstantinov V.O., Denisenko A.D., Gaitskhoki V.S., Schwartz E.I. Two novel low-density lipoprotein receptor gene mutations (E397X and 347delGCC) in St. Petersburg familial hypercholesterolemia. Mol. Genet. Metab. 1998b;65(4):311-314. DOI 10.1006/mgme.1998.2762.Chmara M., Wasag B., Zuk M., Kubalska J., Wegrzyn A., BednarskaMakaruk M., Pronicka E., Wehr H., Defesche J.C., Rynkiewicz A., Limon J. Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. J. Appl. Genet. 2010;51(1):95-106. DOI 10.1007/BF03195716.Chmara M., Wasag B., Zuk M., Kubalska J., Wegrzyn A., BednarskaMakaruk M., Pronicka E., Wehr H., Defesche J.C., Rynkiewicz A., Limon J. Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. J. Appl. Genet. 2010;51(1):95-106. DOI 10.1007/BF03195716.Chora J.R., Medeiros A.M., Alves A.C., Bourbon M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet. Med. 2018;20(6):591-598. DOI 10.1038/gim.2017.151.Chora J.R., Medeiros A.M., Alves A.C., Bourbon M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet. Med. 2018;20(6):591-598. DOI 10.1038/gim.2017.151.Defesche J.C., Gidding S.S., Harada-Shiba M., Hegele R.A., Santos R.D., Wierzbicki A.S. Familial hypercholesterolaemia. Nat. Rev. Dis. Prim. 2017;3:17093. DOI 10.1038/nrdp.2017.93.Defesche J.C., Gidding S.S., Harada-Shiba M., Hegele R.A., Santos R.D., Wierzbicki A.S. Familial hypercholesterolaemia. Nat. Rev. Dis. Prim. 2017;3:17093. DOI 10.1038/nrdp.2017.93.Ershova A.I., Meshkov A.N., Bazhan S.S., Storozhok M.A., Efanov A.Y., Medvedeva I.V., Indukaeva E.V., Danilchenko Y.V., Kuzmina O.K., Barbarash O.L., Deev A.D., Shalnova S.A., Boytsov S.A. The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: a substudy of the ESSE-RF. PLoS One. 2017;12(7):e0181148. DOI 10.1371/journal.pone.0181148.Ershova A.I., Meshkov A.N., Bazhan S.S., Storozhok M.A., Efanov A.Y., Medvedeva I.V., Indukaeva E.V., Danilchenko Y.V., Kuzmina O.K., Barbarash O.L., Deev A.D., Shalnova S.A., Boytsov S.A. The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: a substudy of the ESSE-RF. PLoS One. 2017;12(7):e0181148. DOI 10.1371/journal.pone.0181148.Fouchier S.W., Kastelein J.J., Defesche J.C. Update of the molecular basis of familial hypercholesterolemia in the Netherlands. Hum. Mutat. 2005;26(6):550-556. DOI 10.1002/humu.20256.Fouchier S.W., Kastelein J.J., Defesche J.C. Update of the molecular basis of familial hypercholesterolemia in the Netherlands. Hum. Mutat. 2005;26(6):550-556. DOI 10.1002/humu.20256.Iacocca M.A., Chora J.R., Carrié A., Freiberger T., Leigh S.E., Defesche J.C., Kurtz C.L., DiStefano M.T., Santos R.D., Humphries S.E., Mata P., Jannes C.E., Hooper A.J., Wilemon K.A., Benlian P., O’Connor R., Garcia J., Wand H., Tichy L., Sijbrands E.J., Hegele R.A., Bourbon M., Knowles J.W., ClinGen FH Variant Curation Expert Panel. ClinVar database of global familial hypercholesterolemia-associated DNA variants. Hum. Mutat. 2018;39(11):1631-1640. DOI 10.1002/humu.23634.Iacocca M.A., Chora J.R., Carrié A., Freiberger T., Leigh S.E., Defesche J.C., Kurtz C.L., DiStefano M.T., Santos R.D., Humphries S.E., Mata P., Jannes C.E., Hooper A.J., Wilemon K.A., Benlian P., O’Connor R., Garcia J., Wand H., Tichy L., Sijbrands E.J., Hegele R.A., Bourbon M., Knowles J.W., ClinGen FH Variant Curation Expert Panel. ClinVar database of global familial hypercholesterolemia-associated DNA variants. Hum. Mutat. 2018;39(11):1631-1640. DOI 10.1002/humu.23634.Komarova T.Yu., Golovina A.S., Grudinina N.A., Zakharova F.M., Korneva V.A., Lipovetsky B.M., Serebrenitskaya M.P., Konstantinov V.O., Vasilyev V.B., Mandelshtam M.Yu. New mutations in lowdensity lipoprotein receptor gene in familial hypercholesterolemia patients from Petrozavodsk. Russ. J. Genet. 2013a;49(6):673-676. DOI 10.1134/S1022795413040066.Komarova T.Yu., Golovina A.S., Grudinina N.A., Zakharova F.M., Korneva V.A., Lipovetsky B.M., Serebrenitskaya M.P., Konstantinov V.O., Vasilyev V.B., Mandelshtam M.Yu. New mutations in lowdensity lipoprotein receptor gene in familial hypercholesterolemia patients from Petrozavodsk. Russ. J. Genet. 2013a;49(6):673-676. DOI 10.1134/S1022795413040066.Komarova T.Yu., Golovina A.S., Grudinina N.A., Zakharova F.M., Korneva V.A., Lipovetskii B.M., Serebrenitskaya M.P., Konstantinov V.O., Vasilyev V.B., Mandelshtam M.Yu. “Finnish” mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk. Bull. Exp. Biol. Med. 2013b;155(3):380-383. DOI 10.1007/s10517-013-2159-4.Komarova T.Yu., Golovina A.S., Grudinina N.A., Zakharova F.M., Korneva V.A., Lipovetskii B.M., Serebrenitskaya M.P., Konstantinov V.O., Vasilyev V.B., Mandelshtam M.Yu. “Finnish” mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk. Bull. Exp. Biol. Med. 2013b;155(3):380-383. DOI 10.1007/s10517-013-2159-4.Komarova T.Yu., Korneva V.A., Kuznetsova T.Yu., Golovina A.S., Vasilyev V.B., Mandelshtam M.Yu. Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum. BMC Med. Genet. 2013c;14(1):128. DOI 10.1186/1471-2350-14-128.Komarova T.Yu., Korneva V.A., Kuznetsova T.Yu., Golovina A.S., Vasilyev V.B., Mandelshtam M.Yu. Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum. BMC Med. Genet. 2013c;14(1):128. DOI 10.1186/1471-2350-14-128.Korneva V.A., Bogoslovskaya T.Yu., Kuznetsova T.Yu., Mandelshtam M.Yu., Vasiliev V.B. Familial hypercholesterolemia due to a new mutation in the low density lipoprotein receptor gene. Klinicheskaia Meditsina = Clinical Medicine. 2014;92(7):49-53. (in Russian)Korneva V.A., Bogoslovskaya T.Yu., Kuznetsova T.Yu., Mandelshtam M.Yu., Vasiliev V.B. Familial hypercholesterolemia due to a new mutation in the low density lipoprotein receptor gene. Klinicheskaia Meditsina = Clinical Medicine. 2014;92(7):49-53. (in Russian)Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Murtazina R.Z., Didio A.V., Serebrenitskaya M.P., Konstantinov V.O., Mandelshtam M.Yu., Vasilyev V.B. Clinical case of a patient with family hypercholesterolemia caused by mutation c.1859G>C (p.W620S) in the gene of human low density lipoproteins receptor. Kardiovaskulyarnaya Terapiya i Profilaktika = Cardiovascular Therapy and Prevention. 2015;14(6):52-53. DOI 10.15829/1728-8800-2015-6-52-53. (in Russian)Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Murtazina R.Z., Didio A.V., Serebrenitskaya M.P., Konstantinov V.O., Mandelshtam M.Yu., Vasilyev V.B. Clinical case of a patient with family hypercholesterolemia caused by mutation c.1859G>C (p.W620S) in the gene of human low density lipoproteins receptor. Kardiovaskulyarnaya Terapiya i Profilaktika = Cardiovascular Therapy and Prevention. 2015;14(6):52-53. DOI 10.15829/1728-8800-2015-6-52-53. (in Russian)Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Murtazina R.Z., Didio A.V., Serebrenitskaya M.P., Konstantinov V.O., Mandelshtam M.Yu., Vasilyev V.B. Modern diagnostic abilities of familial hypercholesterolemia before clinical features of atherosclerosis appearance. Ateroscleros i Dislipidemii = Journal of Atherosclerosis and Dyslipidemias. 2016;1:22-32. (in Russian)Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Murtazina R.Z., Didio A.V., Serebrenitskaya M.P., Konstantinov V.O., Mandelshtam M.Yu., Vasilyev V.B. Modern diagnostic abilities of familial hypercholesterolemia before clinical features of atherosclerosis appearance. Ateroscleros i Dislipidemii = Journal of Atherosclerosis and Dyslipidemias. 2016;1:22-32. (in Russian)Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Polyakov D.S., Vasilyev V.B., Orlov A.V., Mandelshtam M.Yu. Cholesterol levels in genetically determined familial hypercholesterolaemia in Russian Karelia. Cholesterol. 2017a;2017:9375818. DOI 10.1155/2017/9375818.Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., Polyakov D.S., Vasilyev V.B., Orlov A.V., Mandelshtam M.Yu. Cholesterol levels in genetically determined familial hypercholesterolaemia in Russian Karelia. Cholesterol. 2017a;2017:9375818. DOI 10.1155/2017/9375818.Korneva V.A., Kuznetsova T.Yu., Komarova T.Yu., Golovina A.S., Mandelshtam M.Yu., Konstantinov V.O., Vasilyev V.B. A case of familial hypercholesterolemia caused by a novel mutation p. FsS65:D129X of human low density lipoprotein receptor gene. Kardiologiia = Cardiology. 2013;53(5):50-54. (in Russian)Korneva V.A., Kuznetsova T.Yu., Komarova T.Yu., Golovina A.S., Mandelshtam M.Yu., Konstantinov V.O., Vasilyev V.B. A case of familial hypercholesterolemia caused by a novel mutation p. FsS65:D129X of human low density lipoprotein receptor gene. Kardiologiia = Cardiology. 2013;53(5):50-54. (in Russian)Korneva V.A., Kuznetsova T.Yu., Murtazina R.Z., Didio A.V., Bogoslovskaya T.Yu., Mandelshtam M.Yu., Vasilyev V.B. The familial hypercholesterolemia caused by a novel human low density lipoprotein receptor gene mutation c.1327 T>C (p.W433R). Kardiologiia = Cardiology. 2017b;57(2):12-16. DOI 10.18565/cardio.2017.2.12-16. (in Russian)Korneva V.A., Kuznetsova T.Yu., Murtazina R.Z., Didio A.V., Bogoslovskaya T.Yu., Mandelshtam M.Yu., Vasilyev V.B. The familial hypercholesterolemia caused by a novel human low density lipoprotein receptor gene mutation c.1327 T>C (p.W433R). Kardiologiia = Cardiology. 2017b;57(2):12-16. DOI 10.18565/cardio.2017.2.12-16. (in Russian)Krapivner S.R., Malyshev P.P., Poltaraus A.B., Kukharchuk V.V., Bochkov V.N. A case of familial hypercholesterolemia caused by a novel mutation D461Y in the low density lipoprotein receptor gene. Kardiologiia = Cardiology. 2001;41(1):92-94. (in Russian)Krapivner S.R., Malyshev P.P., Poltaraus A.B., Kukharchuk V.V., Bochkov V.N. A case of familial hypercholesterolemia caused by a novel mutation D461Y in the low density lipoprotein receptor gene. Kardiologiia = Cardiology. 2001;41(1):92-94. (in Russian)Landrum M.J., Lee J.M., Benson M., Brown G., Chao C., Chitipiralla S., Gu B., Hart J., Hoffman D., Hoover J., Jang W., Katz K., Ovetsky M., Riley G., Sethi A., Tully R., Villamarin-Salomon R., Rubinstein W., Maglott D.R. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862-D868. DOI 10.1093/nar/gkv1222.Landrum M.J., Lee J.M., Benson M., Brown G., Chao C., Chitipiralla S., Gu B., Hart J., Hoffman D., Hoover J., Jang W., Katz K., Ovetsky M., Riley G., Sethi A., Tully R., Villamarin-Salomon R., Rubinstein W., Maglott D.R. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862-D868. DOI 10.1093/nar/gkv1222.Mandelshtam M., Chakir K., Shevtsov S., Golubkov V., Skobeleva N., Lipovetsky B., Konstantinov V., Denisenko A., Gaitskhoki V., Schwartz E. Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia. Hum. Mutat. 1998a;12(4):255-258. DOI 10.1002/(SICI)1098-1004(1998)12:4<255::AID-HUMU6>3.0.CO;2-E.Mandelshtam M., Chakir K., Shevtsov S., Golubkov V., Skobeleva N., Lipovetsky B., Konstantinov V., Denisenko A., Gaitskhoki V., Schwartz E. Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia. Hum. Mutat. 1998a;12(4):255-258. DOI 10.1002/(SICI)1098-1004(1998)12:4<255::AID-HUMU6>3.0.CO;2-E.Mandelshtam M.Ju., Golubkov V.I., Schur Yu.A., Lipovetsky B.M., Gaitskhoki V.S. A novel mutation 347delGCC in the human low density lipoprotein receptor gene. Russ. J. Bioorg. Chem. 1998b;24(10):710-711.Mandelshtam M.Ju., Golubkov V.I., Schur Yu.A., Lipovetsky B.M., Gaitskhoki V.S. A novel mutation 347delGCC in the human low density lipoprotein receptor gene. Russ. J. Bioorg. Chem. 1998b;24(10):710-711.Mandelshtam M.Ju., Lipovetskyi B.M., Schwartzman A.L., Gaitskhoki V.S. A novel deletion in the low density lipoprotein receptor gene in a patient with familial hypercholesterolemia from Petersburg. Hum. Mutat. 1993;2(4):256-260. DOI 10.1002/humu.1380020404.Mandelshtam M.Ju., Lipovetskyi B.M., Schwartzman A.L., Gaitskhoki V.S. A novel deletion in the low density lipoprotein receptor gene in a patient with familial hypercholesterolemia from Petersburg. Hum. Mutat. 1993;2(4):256-260. DOI 10.1002/humu.1380020404.Mandelshtam M.Yu., Maslennikov A.B. Study of familial hypercholesterolemia molecular genetics in Russia. In: Maslennikov A.B. (Ed.) Molecular Technologies in Practical Medicine. Novosibirsk: Publ. House “Manuskript”, 2001;58-64. (in Russian)Mandelshtam M.Yu., Maslennikov A.B. Study of familial hypercholesterolemia molecular genetics in Russia. In: Maslennikov A.B. (Ed.) Molecular Technologies in Practical Medicine. Novosibirsk: Publ. House “Manuskript”, 2001;58-64. (in Russian)Meshkov A., Ershova A., Kiseleva A., Zotova E., Sotnikova E., Petukhova A., Zharikova A., Malyshev P., Rozhkova T., Blokhina A., Limonova A., Ramensky V., Divashuk M., Khasanova Z., Bukaeva A., Kurilova O., Skirko O., Pokrovskaya M., Mikova V., Snigir E., Akinshina A., Mitrofanov S., Kashtanova D., Makarov V., Kukharchuk V., Boytsov S., Yudin S., Drapkina O. The LDLR, APOB, and PCSK9 variants of index patients with familial hypercholesterolemia in Russia. Genes. 2021a;12(1):66. DOI 10.3990/genes12010066.Meshkov A., Ershova A., Kiseleva A., Zotova E., Sotnikova E., Petukhova A., Zharikova A., Malyshev P., Rozhkova T., Blokhina A., Limonova A., Ramensky V., Divashuk M., Khasanova Z., Bukaeva A., Kurilova O., Skirko O., Pokrovskaya M., Mikova V., Snigir E., Akinshina A., Mitrofanov S., Kashtanova D., Makarov V., Kukharchuk V., Boytsov S., Yudin S., Drapkina O. The LDLR, APOB, and PCSK9 variants of index patients with familial hypercholesterolemia in Russia. Genes. 2021a;12(1):66. DOI 10.3990/genes12010066.Meshkov A.N., Ershova A.I., Kiseleva A.V., Shalnova S.A., Drapkina O.M., Boytsov S.A. On behalf of the FH-ESSERF Investigators. The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian Federation: the FH-ESSE-RF study. J. Pers. Med. 2021b;11(6):464. DOI 10.3390/jpm11060464.Meshkov A.N., Ershova A.I., Kiseleva A.V., Shalnova S.A., Drapkina O.M., Boytsov S.A. On behalf of the FH-ESSERF Investigators. The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian Federation: the FH-ESSE-RF study. J. Pers. Med. 2021b;11(6):464. DOI 10.3390/jpm11060464.Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Familial hypercholesterolemia in Russia: genetic and phenotypic characteristics. Terapevticheskiy Arkhiv = Therapeutic Archive. 2009;81(9):23-28. (in Russian)Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Familial hypercholesterolemia in Russia: genetic and phenotypic characteristics. Terapevticheskiy Arkhiv = Therapeutic Archive. 2009;81(9):23-28. (in Russian)Meshkov A.N., Stambolsky D.V., Krapivner S.R., Bochkov V.N., Kukharchuk V.V., Malyshev P.P. Low density lipoprotein receptor gene mutations in patients with clinical diagnosis of familial hypercholesterolemia. Kardiologiia = Cardiology. 2004;44(9):58-61. (in Russian)Meshkov A.N., Stambolsky D.V., Krapivner S.R., Bochkov V.N., Kukharchuk V.V., Malyshev P.P. Low density lipoprotein receptor gene mutations in patients with clinical diagnosis of familial hypercholesterolemia. Kardiologiia = Cardiology. 2004;44(9):58-61. (in Russian)Miroshnikova V.V., Romanova O.V., Ivanova O.N., Fedyakov M.A., Panteleeva A.A., Barbitoff Y.A., Muzalevskaya M.M., Urazgildeeva S.A., Gurevich V.S., Urazov S.P., Scherbak S.G., Sarana A.M., Semenova N.A., Anisimova I.V., Guseva D.M., Pchelina S.N., Glotov A.S., Zakharova E.Y., Glotov O.S. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomed. Rep. 2021;14(1):15. DOI 10.3892/br.2020.1391.Miroshnikova V.V., Romanova O.V., Ivanova O.N., Fedyakov M.A., Panteleeva A.A., Barbitoff Y.A., Muzalevskaya M.M., Urazgildeeva S.A., Gurevich V.S., Urazov S.P., Scherbak S.G., Sarana A.M., Semenova N.A., Anisimova I.V., Guseva D.M., Pchelina S.N., Glotov A.S., Zakharova E.Y., Glotov O.S. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomed. Rep. 2021;14(1):15. DOI 10.3892/br.2020.1391.Mozas P., Castillo S., Tejedor D., Reyes G., Alonso R., Franco M., Saenz P., Fuentes F., Almagro F., Mata P., Pocoví M. Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Hum. Mutat. 2004;24(2):187. DOI 10.1002/humu.9264.Mozas P., Castillo S., Tejedor D., Reyes G., Alonso R., Franco M., Saenz P., Fuentes F., Almagro F., Mata P., Pocoví M. Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Hum. Mutat. 2004;24(2):187. DOI 10.1002/humu.9264.Pirillo A., Garlaschelli K., Arca M., Averna M., Bertolini S., Calandra S., Tarugi P., Catapano A.L., LIPIGEN Group. Spectrum of mutations in Italian patients with familial hypercholesterolemia: new results from the LIPIGEN study. Atheroscler. Suppl. 2017;29:17-24. DOI 10.1016/j.atherosclerosissup.2017.07.002.Pirillo A., Garlaschelli K., Arca M., Averna M., Bertolini S., Calandra S., Tarugi P., Catapano A.L., LIPIGEN Group. Spectrum of mutations in Italian patients with familial hypercholesterolemia: new results from the LIPIGEN study. Atheroscler. Suppl. 2017;29:17-24. DOI 10.1016/j.atherosclerosissup.2017.07.002.Semenova A.E., Sergienko I.V., García-Giustiniani D., Monserrat L., Popova A.B., Nozadze D.N., Ezhov M. Verification of underlying genetic cause in a cohort of Russian patients with familial hypercholesterolemia using targeted next generation sequencing. J. Cardiovasc. Dev. Dis. 2020;7(2):16. DOI 10.3390/jcdd7020016.Semenova A.E., Sergienko I.V., García-Giustiniani D., Monserrat L., Popova A.B., Nozadze D.N., Ezhov M. Verification of underlying genetic cause in a cohort of Russian patients with familial hypercholesterolemia using targeted next generation sequencing. J. Cardiovasc. Dev. Dis. 2020;7(2):16. DOI 10.3390/jcdd7020016.Shakhtshneider E.V., Ivanoshchuk D.E., Fishman V.S., Belokopytova P.S., Orlov P.S., Timoshchenko O.V., Voevoda M.I. Target sequencing of genes LDLR, APOB, PCSK9, LDLRAP1 and gene cluster APOA5-A4-C3-A1 in patients with familial hypercholesterolemia. Kompleksnye Problemy Serdechnososydistykh Zabolevaniy = Complex Issues of Cardiovascular Diseases. 2019a;8(S3-2):71. (in Russian)Shakhtshneider E.V., Ivanoshchuk D.E., Fishman V.S., Belokopytova P.S., Orlov P.S., Timoshchenko O.V., Voevoda M.I. Target sequencing of genes LDLR, APOB, PCSK9, LDLRAP1 and gene cluster APOA5-A4-C3-A1 in patients with familial hypercholesterolemia. Kompleksnye Problemy Serdechnososydistykh Zabolevaniy = Complex Issues of Cardiovascular Diseases. 2019a;8(S3-2):71. (in Russian)Shakhtshneider E.V., Ivanoshchuk D.E., Makarenkova K.V., Orlov P.S., Timoshchenko O.V., Bazhan S.S., Nikitin Y.P., Voevoda M.I. Cascade genetic screening in diagnostics of heterozygous familial hypercholesterolemia: clinical case. Russian Journal of Cardiology. 2017;6(146):178-179. DOI 10.15829/1560-4071-2017-6-178-179. (in Russian)Shakhtshneider E.V., Ivanoshchuk D.E., Makarenkova K.V., Orlov P.S., Timoshchenko O.V., Bazhan S.S., Nikitin Y.P., Voevoda M.I. Cascade genetic screening in diagnostics of heterozygous familial hypercholesterolemia: clinical case. Russian Journal of Cardiology. 2017;6(146):178-179. DOI 10.15829/1560-4071-2017-6-178-179. (in Russian)Shakhtshneider E., Ivanoshchuk D., Orlov P., Timoshchenko O., Voevoda M. Analysis of the LDLR, APOB, PCSK9 and LDLRAP1 genes variability in patients with familial hypercholesterolemia in West Siberia using targeted high throughput resequencing. Atherosclerosis. 2019b;287:e285. DOI 10.1016/j.atherosclerosis.2019.06.883.Shakhtshneider E., Ivanoshchuk D., Orlov P., Timoshchenko O., Voevoda M. Analysis of the LDLR, APOB, PCSK9 and LDLRAP1 genes variability in patients with familial hypercholesterolemia in West Siberia using targeted high throughput resequencing. Atherosclerosis. 2019b;287:e285. DOI 10.1016/j.atherosclerosis.2019.06.883.Shakhtschneider E., Ivanoshchuk D., Timoshenko O., Orlov P., Semayev S., Valeev E., Goonko A., Ladygina N., Voevoda M. Analysis of rare variants in genes related to lipid metabolism in patients with familial hypercholesterolemia in Western Siberia (Russia). J. Pers. Med. 2021;11(11):1232. DOI 10.3990/jpm11111232.Shakhtschneider E., Ivanoshchuk D., Timoshenko O., Orlov P., Semayev S., Valeev E., Goonko A., Ladygina N., Voevoda M. Analysis of rare variants in genes related to lipid metabolism in patients with familial hypercholesterolemia in Western Siberia (Russia). J. Pers. Med. 2021;11(11):1232. DOI 10.3990/jpm11111232.Tatishcheva Yu.A., Mandelshtam M.Yu., Golubkov V.I., Lipovetsky B.M., Gaitskhoki V.S. Four new mutations and two polymorphic variants of the low-density lipoprotein receptor gene in familial hypercholesterolemia patients from St. Petersburg. Russ. J. Genet. 2001;37(9):1082-1087. DOI 10.1023/A:1011973817437.Tatishcheva Yu.A., Mandelshtam M.Yu., Golubkov V.I., Lipovetsky B.M., Gaitskhoki V.S. Four new mutations and two polymorphic variants of the low-density lipoprotein receptor gene in familial hypercholesterolemia patients from St. Petersburg. Russ. J. Genet. 2001;37(9):1082-1087. DOI 10.1023/A:1011973817437.Tichý L., Freiberger T., Zapletalová P., Soška V., Ravčuková B., Fajkusová L. The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotypephenotype correlations. Atherosclerosis. 2012;223(2):401-408. DOI 10.1016/j.atherosclerosis.2012.05.014.Tichý L., Freiberger T., Zapletalová P., Soška V., Ravčuková B., Fajkusová L. The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotypephenotype correlations. Atherosclerosis. 2012;223(2):401-408. DOI 10.1016/j.atherosclerosis.2012.05.014.Vasilyev V., Zakharova F., Bogoslovskaya T., Mandelshtam M. Familial hypercholesterolemia in Russia: three decades of genetic studies. Front. Genet. 2020;11:550591. DOI 10.3389/fgene.2020.550591.Vasilyev V., Zakharova F., Bogoslovskaya T., Mandelshtam M. Familial hypercholesterolemia in Russia: three decades of genetic studies. Front. Genet. 2020;11:550591. DOI 10.3389/fgene.2020.550591.Voevoda M.I., Kulikov I.V., Shakhtshneider E.V., Maksimov V.N., Pilipenko I.V., Tereschenko I.P., Kobzev E.F., Romaschenko A.G., Nikitin Yu.P. The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population. Russ. J. Genet. 2008;44(10):1191-1194. DOI 10.1134/S1022795408100074.Voevoda M.I., Kulikov I.V., Shakhtshneider E.V., Maksimov V.N., Pilipenko I.V., Tereschenko I.P., Kobzev E.F., Romaschenko A.G., Nikitin Yu.P. The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population. Russ. J. Genet. 2008;44(10):1191-1194. DOI 10.1134/S1022795408100074.Zakharova F.M., Damgaard D., Mandelshtam M.Y., Golubkov V.I., Nissen P.H., Nilsen G.G., Stenderup A., Lipovetsky B.M., Konstantinov V.O., Denisenko A.D., Vasilyev V.B., Faergeman O. Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med. Genet. 2005;6:6. DOI 10.1186/1471-2350-6-6.Zakharova F.M., Damgaard D., Mandelshtam M.Y., Golubkov V.I., Nissen P.H., Nilsen G.G., Stenderup A., Lipovetsky B.M., Konstantinov V.O., Denisenko A.D., Vasilyev V.B., Faergeman O. Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med. Genet. 2005;6:6. DOI 10.1186/1471-2350-6-6.Zakharova F.M., Golubkov V.I., Mandelshtam M.Ju., Lipovetskii B.M., Gaitskhoki V.S. Identification of novel missense mutation G571E, novel silent mutation H229H, nonsense mutation C74X, and four single nucleotide polymorphisms in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg. Russ. J. Bioorg. Chem. 2001;27:349-351. DOI 10.1023/a:1012300632671.Zakharova F.M., Golubkov V.I., Mandelshtam M.Ju., Lipovetskii B.M., Gaitskhoki V.S. Identification of novel missense mutation G571E, novel silent mutation H229H, nonsense mutation C74X, and four single nucleotide polymorphisms in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg. Russ. J. Bioorg. Chem. 2001;27:349-351. DOI 10.1023/a:1012300632671.Zakharova F.M., Tatishcheva Yu.A., Golubkov V.I., Lipovetsky B.M., Konstantinov V.O., Denisenko A.D., Faergeman O., Vasilyev V.B., Mandelshtam M.Yu. Familial hypercholesterolemia in St. Petersburg: diversity of mutations argues against a strong founder effect. Russ. J. Genet. 2007;43(9):1046-1052. DOI 10.1134/S1022795407090116.Zakharova F.M., Tatishcheva Yu.A., Golubkov V.I., Lipovetsky B.M., Konstantinov V.O., Denisenko A.D., Faergeman O., Vasilyev V.B., Mandelshtam M.Yu. Familial hypercholesterolemia in St. Petersburg: diversity of mutations argues against a strong founder effect. Russ. J. Genet. 2007;43(9):1046-1052. DOI 10.1134/S1022795407090116.

The authors declare that there are no conflicts of interest present.