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Published on: September 15, 2018
Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using
Valentina V Miroshnikova1, Olga V Romanova2,3, Olga N Ivanova4
1Laboratory of Human Molecular Genetics, Molecular and Radiation Biophysics Department, Petersburg Nuclear Physics Institute, National Research Center 'Kurchatov Institute', Gatchina 188300, Russian Federation.
Insights
This study identified seven novel LDLR gene variants and expanded the spectrum of mutations for familial hypercholesterolemia (FH) in Russian patients. Next-generation sequencing revealed higher mutation detection rates in children compared to adults.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Diseases
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL cholesterol.
- Mutations in LDLR, APOB, and PCSK9 genes are common causes of FH.
- The spectrum of FH-associated mutations in the Russian population remains incompletely characterized.
Purpose of the Study:
- To investigate the spectrum of mutations in FH-associated genes in Russian patients.
- To identify novel pathogenic variants contributing to FH in this population.
- To compare mutation detection rates between adult and pediatric FH cohorts.
Main Methods:
- Next-generation sequencing (NGS) was employed for mutation screening.
- 59 unrelated patients with definite or possible FH were recruited.
- Patients were stratified into adult (n=31) and children/adolescent (n=28) groups.
Main Results:
- FH-associated variants were detected in 58% of adults and 89% of children/adolescents.
- Seven novel pathogenic or likely pathogenic LDLR variants were identified.
- Previously reported variants were found in 33 patients, with LDLR p.(Gly592Glu) being prevalent in 10% of cases.
Conclusions:
- The study identified seven novel LDLR variants, broadening the known mutation spectrum for FH in Russia.
- Mutation detection rates were significantly higher in the pediatric cohort.
- The findings highlight the genetic heterogeneity of FH and the importance of comprehensive genetic screening.
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.
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