Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing

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Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. / Miroshnikova, Valentina V.; Romanova, Olga V.; Ivanova, Olga N.; Fedyakov, Mikhail A.; Panteleeva, Alexandra A.; Barbitoff, Yury A.; Muzalevskaya, Maria V.; Urazgildeeva, Sorejya A.; Gurevich, Victor S.; Urazov, Stanislav P.; Scherbak, Sergey G.; Sarana, Andrey M.; Semenova, Natalia A.; Anisimova, Inga V.; Guseva, Darya M.; Pchelina, Sofya N.; Glotov, Andrey S.; Zakharova, Ekaterina Y.; Glotov, Oleg S.

In: Biomedical Reports, Vol. 14, No. 1, 15, 17.11.2020, p. 15.

Research output: Contribution to journal › Article › peer-review

Author

Miroshnikova, Valentina V. ; Romanova, Olga V. ; Ivanova, Olga N. ; Fedyakov, Mikhail A. ; Panteleeva, Alexandra A. ; Barbitoff, Yury A. ; Muzalevskaya, Maria V. ; Urazgildeeva, Sorejya A. ; Gurevich, Victor S. ; Urazov, Stanislav P. ; Scherbak, Sergey G. ; Sarana, Andrey M. ; Semenova, Natalia A. ; Anisimova, Inga V. ; Guseva, Darya M. ; Pchelina, Sofya N. ; Glotov, Andrey S. ; Zakharova, Ekaterina Y. ; Glotov, Oleg S. / Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. In: Biomedical Reports. 2020 ; Vol. 14, No. 1. pp. 15.

BibTeX

@article{a88110564fda49fbaef573d4a15e6aa5,

title = "Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing",

abstract = "Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the LDLR, APOB and PSCK9 genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the LDLR gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the LDLR gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had APOB mutations and two had ABCG5/G8 mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the LDLR gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had APOB mutations, as well as ABCG8 and LIPA mutations, being found in different patients. The present study reported seven novel LDLR variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the LDLR, APOB, ABCG5/8 and LIPA genes were observed in 33 patients. The LDLR p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the LDLR gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.",

keywords = "Familial hyper-cholesterolemia, LDLR, Next generation sequencing, MOLECULAR CHARACTERIZATION, ABCG5, next generation sequencing, AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA, ATHEROSCLEROSIS, SITOSTEROLEMIA, MISSENSE MUTATIONS, familial hypercholesterolemia, SWEDISH PATIENTS, LIPOPROTEIN RECEPTOR GENE, SPECTRUM, NONSENSE MUTATION",

author = "Miroshnikova, {Valentina V.} and Romanova, {Olga V.} and Ivanova, {Olga N.} and Fedyakov, {Mikhail A.} and Panteleeva, {Alexandra A.} and Barbitoff, {Yury A.} and Muzalevskaya, {Maria V.} and Urazgildeeva, {Sorejya A.} and Gurevich, {Victor S.} and Urazov, {Stanislav P.} and Scherbak, {Sergey G.} and Sarana, {Andrey M.} and Semenova, {Natalia A.} and Anisimova, {Inga V.} and Guseva, {Darya M.} and Pchelina, {Sofya N.} and Glotov, {Andrey S.} and Zakharova, {Ekaterina Y.} and Glotov, {Oleg S.}",

year = "2020",

month = nov,

day = "17",

doi = "10.3892/br.2020.1391",

language = "English",

volume = "14",

pages = "15",

journal = "Biomedical Reports",

issn = "2049-9434",

publisher = "Spandidos Publications",

number = "1",

}

RIS

TY - JOUR

T1 - Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing

AU - Miroshnikova, Valentina V.

AU - Romanova, Olga V.

AU - Ivanova, Olga N.

AU - Fedyakov, Mikhail A.

AU - Panteleeva, Alexandra A.

AU - Barbitoff, Yury A.

AU - Muzalevskaya, Maria V.

AU - Urazgildeeva, Sorejya A.

AU - Gurevich, Victor S.

AU - Urazov, Stanislav P.

AU - Scherbak, Sergey G.

AU - Sarana, Andrey M.

AU - Semenova, Natalia A.

AU - Anisimova, Inga V.

AU - Guseva, Darya M.

AU - Pchelina, Sofya N.

AU - Glotov, Andrey S.

AU - Zakharova, Ekaterina Y.

AU - Glotov, Oleg S.

PY - 2020/11/17

Y1 - 2020/11/17

N2 - Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the LDLR, APOB and PSCK9 genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the LDLR gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the LDLR gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had APOB mutations and two had ABCG5/G8 mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the LDLR gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had APOB mutations, as well as ABCG8 and LIPA mutations, being found in different patients. The present study reported seven novel LDLR variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the LDLR, APOB, ABCG5/8 and LIPA genes were observed in 33 patients. The LDLR p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the LDLR gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.

AB - Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the LDLR, APOB and PSCK9 genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the LDLR gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the LDLR gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had APOB mutations and two had ABCG5/G8 mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the LDLR gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had APOB mutations, as well as ABCG8 and LIPA mutations, being found in different patients. The present study reported seven novel LDLR variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the LDLR, APOB, ABCG5/8 and LIPA genes were observed in 33 patients. The LDLR p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the LDLR gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.

KW - Familial hyper-cholesterolemia

KW - LDLR

KW - Next generation sequencing

KW - MOLECULAR CHARACTERIZATION

KW - ABCG5

KW - next generation sequencing

KW - AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA

KW - ATHEROSCLEROSIS

KW - SITOSTEROLEMIA

KW - MISSENSE MUTATIONS

KW - familial hypercholesterolemia

KW - SWEDISH PATIENTS

KW - LIPOPROTEIN RECEPTOR GENE

KW - SPECTRUM

KW - NONSENSE MUTATION

UR - http://www.scopus.com/inward/record.url?scp=85097306671&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/68486ff4-7ee2-338a-8321-0c6cc02d7f76/

U2 - 10.3892/br.2020.1391

DO - 10.3892/br.2020.1391

M3 - Article

C2 - 33269076

AN - SCOPUS:85097306671

VL - 14

SP - 15

JO - Biomedical Reports

JF - Biomedical Reports

SN - 2049-9434

IS - 1

M1 - 15

ER -

ID: 73039502