Cascade Genetic Screening in Diagnostics of Heterozygous Familial Hypercholesterolemia: Clinical Case

Shakhtshneider, E.; Ivanoshchuk, D.; Makarenkova, K.; Орлов, П. С.; Тимощенко, О. В.; Бажан, С С; Никитин, Ю. П.; Воевода, М. И.

doi:10.15829/1560-4071-2017-6-178-179

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…The rs879255191 variant in the regulatory region of LDLR has previously been described by us in proband P24 with familial hypercholesterolemia and in his two children (patients P25 and P26) with hyperlipidemia (7 and 8 years old) [35,36]. Variant c.2389 + 5G > A is located in highly conserved dinucleotide AG at the splice donor site of intron 16 of LDLR.…”

Section: Ldlrmentioning

confidence: 77%

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Shakhtshneider

Ivanoshchuk

Тимощенко

et al. 2021

JPM

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The aim of this work was to identify genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype). For patients without functionally significant substitutions in the above genes, multiplex ligation-dependent probe amplification was conducted to determine bigger mutations (deletions and/or duplications) in the LDLR promoter and exons. A clinically significant variant in some gene associated with familial hypercholesterolemia was identified in 47.5% of the subjects. Clinically significant variants in the LDLR gene were identified in 19 probands (73.1% of all variants identified in probands); in three probands (11.5%), pathogenic variants were found in the APOB gene; and in four probands (15.4%), rare, clinically significant variants were identified in genes LPL, SREBF1, APOC3, and ABCG5. In 12 (85.7%) of 14 children of the probands, clinically significant variants were detectable in genes associated with familial hypercholesterolemia. The use of clinical criteria, targeted sequencing, and multiplex ligation-dependent probe amplification makes it possible to identify carriers of rare clinically significant variants in a wide range of lipid metabolism genes and to investigate their influence on phenotypic manifestations of familial hypercholesterolemia.

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Section: Ldlrmentioning

confidence: 77%

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Shakhtshneider

Ivanoshchuk

Тимощенко

et al. 2021

JPM

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“…Currently most of the mutations found are specific for each of these cities, and a significantly smaller proportion is common with other regions. Thus, the largest number of pathogenic or probably pathogenic variants in Russia (101) was found only in Moscow (Krapivner et al, 2001;Meshkov et al, 2004Meshkov et al, , 2009Meshkov et al, , 2021aAverkova et al, 2018;Semenova et al, 2020), 35 variants were found only in St. Petersburg (Mandelshtam et al, 1993;Zakharova et al, 2001Zakharova et al, , 2005Zakharova et al, , 2007Tatishcheva et al, 2001), 23 -only in Novosibirsk (Voevoda et al, 2008;Shakhtshneider et al, 2017Shakhtshneider et al, , 2019a, 11 -only in Petrozavodsk (Komarova et al, 2013a-c;Korneva et al, 2013Korneva et al, , 2014Korneva et al, , 2017a, 33 -in other regions, sometimes in several regions simultaneously (Meshkov et al, 2021b). Zakharova et al, 2001Zakharova et al, , 2007Voevoda et al, 2008;Semenova et al, 2020;Meshkov et al, 2021a, b Austria, Belgium, Brazil, Greece, Canada, Germany, The Czech Republic, Italy, The Netherlands, Norway, Poland, Portugal, Spain, USA, etc.…”

Section: Resultsmentioning

confidence: 99%

“…All available literature concerning LDLR gene mutations in the Russian population was analyzed. As a result, a summarizing table was compiled that significantly expands our knowledge about the spectrum of mutations in Russia, as compared to previously published data (Mandelshtam et al, 1993(Mandelshtam et al, , 1998aChakir et al, 1998a, b;Krapivner et al, 2001;Mandelshtam, Maslennikov, 2001;Tatishcheva et al, 2001;Zakharova et al, 2001Zakharova et al, , 2005Zakharova et al, , 2007Meshkov et al, 2004Meshkov et al, , 2009Meshkov et al, , 2021aVoevoda et al, 2008;Komarova et al, 2013a-c;Korneva et al, 2013Korneva et al, -2016Korneva et al, , 2017aShakhtshneider et al, 2017Shakhtshneider et al, , 2019aShakhtshneider et al, , b, 2021Averkova et al, 2018;Semenova et al, 2020) (Supplementary Table ) 1 .…”

Section: Methodsmentioning

confidence: 99%

Analysis of the low density lipoprotein receptor gene (<i>LDLR</i>) mutation spectrum in Russian familial hypercholesterolemia

et al. 2022

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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.

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“…This phenotype can be explained by exon skipping or intron retention (Inoue et al, 2004). Splicing sites affected by mutations have been described for many pathological phenotypes: neurofibromatosis type 1 (Jang et al, 2016), familial hypercholesterolemia (Shakhtshneider et al, 2017), Wiskott-Aldrich syndrome and chronic colitis (Esmaeilzadeh et al, 2018), hypophosphatemic rickets (Ma et al, 2015), and others. Mutations affecting splicing have been found not only in canonical splicing sites but also in introns and exons and may have a tissue-specific effect, as in familial dysautonomia (Slaugenhaupt et al, 2001;Abramowicz, Gos, 2018).…”

Section: Discussionmentioning

confidence: 99%

A rare splice site mutation in the gene encoding glucokinase/hexokinase 4 in a patient with MODY type 2

et al. 2020

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The article presents a variant of maturity onset diabetes of the young type 2, caused by a rare mutation in the GCK gene. Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes with an autosomal dominant type of inheritance, an onset at a young age, and a primary defect in pancreatic β-cell function. This type of diabetes is different from classical types of diabetes mellitus (DM1 and DM2) in its clinical course, treatment strategies, and prognosis. Clinical manifestations of MODY are heterogeneous and may vary even among members of the same family, i. e., carriers of identical mutations. This phenotypic variation is due to the interaction of mutations with different genetic backgrounds and the influence of environmental factors (e. g., lifestyle). Using next-generation sequencing technology, the c.580-1G>A substitution (IVS5 -1G>A, rs1554335421) located in an acceptor splice site of intron 5 of the GCK gene was found in a proband. The identified variant cosegregated with a pathological phenotype in the examined family members. The GCK gene encodes glucokinase (hexokinase 4), which catalyzes the first step in a large number of glucose metabolic pathways such as glycolysis. Mutations in this gene are the cause of MODY2. The illness is characterized by an insignificant increase in the fasting glucose level, is a well-controlled disease without medication, and has a low prevalence of micro-and macrovascular complications of diabetes. The presented case of MODY2 reveals the clinical significance of a mutation in the splice site of the GCK gene. When nonclassical diabetes mellitus is being diagnosed in young people and pregnant women, genetic testing is needed to verify the diagnosis and to select the optimal treatment method.

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Cascade Genetic Screening in Diagnostics of Heterozygous Familial Hypercholesterolemia: Clinical Case

Cited by 9 publications

References 2 publications

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Analysis of the low density lipoprotein receptor gene (<i>LDLR</i>) mutation spectrum in Russian familial hypercholesterolemia

A rare splice site mutation in the gene encoding glucokinase/hexokinase 4 in a patient with MODY type 2

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