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Mr. Rostislav Skitchenko
ITMO University, St. Petersburg, Russia

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Case report
Published: 20 November 2020 in BMC Medical Genomics
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Background Triphalangeal thumb-polysyndactyly syndrome (TPT-PS) is a rare well-defined autosomal dominant disorder characterized by long thumbs with three phalanges combined with pre- and postaxial polydactyly/syndactyly of limbs. By now, the syndrome has been reported in several large families from different ethnic backgrounds, with a high degree of inter- and intrafamilial variability. The genome locus responsible for TPT-PS has been mapped to the 7q36.3 region harboring a long-range sonic hedgehog (SHH) regulatory sequence (ZRS). Both single-nucleotide variants and complete duplications of ZRS were shown to cause TPT-PS and similar limb phenotypes. TPT-PS usually forms as isolated limb pathology not associated with additional malformations, in particular, with cardiovascular abnormalities. Case presentation Here we report on a rare Russian neonatal case of TPT-PS combined with severe congenital heart disease, namely double outlet right ventricle, and microphthalmia with optic disc coloboma. Pedigree analysis revealed TPT-PS of various expressivity in 10 family members throughout five generations, while the cardiac defect and the eye pathology were detected only in the proband. To extend the knowledge on genotype–phenotype spectrum of TPT-PS, the careful clinical and genomic analysis of the family was performed. High-resolution array-based comparative genomic hybridization (array-CGH) revealed a ~ 300 kb microduplication of 7q36.3 locus (arr[GRCh37] 7q36.3(156385810_156684811) × 3) that co-segregated with TPT-PS in the proband and her mother. The duplication encompassed three genes including LMBR1, the intron 5 of which is known to harbor ZRS. Based on whole-exome sequencing data, no additional pathogenic mutations or variants of uncertain clinical significance were found in morbid cardiac genes or genes associated with a microphthalmia/anophthalmia/coloboma spectrum of ocular malformations. Conclusions The results support the previous data, indicating that complete ZRS duplication underlies TPT-PS, and suggest a broader phenotypic impact of the 7q36.3 microduplication. Potential involvement of the 7q36.3 microduplication in the patient’s cardiac and eye malformations is discussed. However, the contribution of some additional genetic/epigenetic factors to the complex patient`s phenotype cannot be excluded entirely. Further comprehensive functional studies are needed to prove the possible involvement of the 7q36.3 locus in congenital heart disease and eye pathology.

ACS Style

Anna Zlotina; Olesia Melnik; Yulia Fomicheva; Rostislav Skitchenko; Alexey Sergushichev; Elena Shagimardanova; Oleg Gusev; Guzel Gazizova; Tatiana Loevets; Tatiana Vershinina; Ivan Kozyrev; Mikhail Gordeev; Elena Vasichkina; Tatiana Pervunina; Anna Kostareva. A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report. BMC Medical Genomics 2020, 13, 1 -9.

AMA Style

Anna Zlotina, Olesia Melnik, Yulia Fomicheva, Rostislav Skitchenko, Alexey Sergushichev, Elena Shagimardanova, Oleg Gusev, Guzel Gazizova, Tatiana Loevets, Tatiana Vershinina, Ivan Kozyrev, Mikhail Gordeev, Elena Vasichkina, Tatiana Pervunina, Anna Kostareva. A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report. BMC Medical Genomics. 2020; 13 (1):1-9.

Chicago/Turabian Style

Anna Zlotina; Olesia Melnik; Yulia Fomicheva; Rostislav Skitchenko; Alexey Sergushichev; Elena Shagimardanova; Oleg Gusev; Guzel Gazizova; Tatiana Loevets; Tatiana Vershinina; Ivan Kozyrev; Mikhail Gordeev; Elena Vasichkina; Tatiana Pervunina; Anna Kostareva. 2020. "A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report." BMC Medical Genomics 13, no. 1: 1-9.

Preprint content
Published: 18 August 2020
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Accurate annotation of putative loss-of-function (pLoF) variants is an important problem in human genomics and disease, which recently drew substantial attention. Since such variants in disease-related genes are under strong negative selection, their frequency across major ancestral groups is expected to be highly similar. In this study, we tested this assumption by systematically assessing the presence of highly population-specific protein-truncating variants (PTVs) in human genes using latest population-scale data. We discovered an unexpectedly high incidence of population-specific PTVs in all major ancestral groups. This does not conform to a recently proposed model, indicating either systemic differences in disease penetrance in different human populations, or a failure of current annotation criteria to accurately predict the loss-of-function potential of PTVs. We show that low-confidence pLoF variants are enriched in genes with non-uniform PTV count distribution, and developed a computational tool called LoFfeR that can efficiently predict tolerated pLoF variants. To evaluate the performance of LoFfeR, we use a set of known pathogenic and benign PTVs from the ClinVar database, and show that LoFfeR allows for a more accurate annotation of low-confidence pLoF variants compared to existing methods. Notably, only 4.4% of protein-truncating gnomAD SNPs in canonical transcripts can be filtered out using a recommended threshold value of the recently proposed pext score, while up to 10.9% of such variants are filtered using LoFfeR with the same false positive rate. Hence, we believe that LoFfeR can be used for additional filtering of low-confidence pLoF variants in population genomics and medical genetics studies.

ACS Style

Rostislav K. Skitchenko; Julia S. Kornienko; Evgeniia M. Maksiutenko; Andrey S. Glotov; Alexander V. Predeus; Yury A. Barbitoff. Harnessing population-specific protein truncating variants to improve the annotation of loss-of-function alleles. 2020, 1 .

AMA Style

Rostislav K. Skitchenko, Julia S. Kornienko, Evgeniia M. Maksiutenko, Andrey S. Glotov, Alexander V. Predeus, Yury A. Barbitoff. Harnessing population-specific protein truncating variants to improve the annotation of loss-of-function alleles. . 2020; ():1.

Chicago/Turabian Style

Rostislav K. Skitchenko; Julia S. Kornienko; Evgeniia M. Maksiutenko; Andrey S. Glotov; Alexander V. Predeus; Yury A. Barbitoff. 2020. "Harnessing population-specific protein truncating variants to improve the annotation of loss-of-function alleles." , no. : 1.

Journal article
Published: 23 March 2020 in Toxins
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Bacillus thuringiensis (Bt) is a natural pathogen of insects and some other groups of invertebrates that produces three-domain Cry (3d-Cry) toxins, which are highly host-specific pesticidal proteins. These proteins represent the most commonly used bioinsecticides in the world and are used for commercial purposes on the market of insecticides, being convergent with the paradigm of sustainable growth and ecological development. Emerging resistance to known toxins in pests stresses the need to expand the list of known toxins to broaden the horizons of insecticidal approaches. For this purpose, we have elaborated a fast and user-friendly tool called CryProcessor, which allows productive and precise mining of 3d-Cry toxins. The only existing tool for mining Cry toxins, called a BtToxin_scanner, has significant limitations such as limited query size, lack of accuracy and an outdated database. In order to find a proper solution to these problems, we have developed a robust pipeline, capable of precise 3d-Cry toxin mining. The unique feature of the pipeline is the ability to search for Cry toxins sequences directly on assembly graphs, providing an opportunity to analyze raw sequencing data and overcoming the problem of fragmented assemblies. Moreover, CryProcessor is able to predict precisely the domain layout in arbitrary sequences, allowing the retrieval of sequences of definite domains beyond the bounds of a limited number of toxins presented in CryGetter. Our algorithm has shown efficiency in all its work modes and outperformed its analogues on large amounts of data. Here, we describe its main features and provide information on its benchmarking against existing analogues. CryProcessor is a novel, fast, convenient, open source (https://github.com/lab7arriam/cry_processor), platform-independent, and precise instrument with a console version and elaborated web interface (https://lab7.arriam.ru/tools/cry_processor). Its major merits could make it possible to carry out massive screening for novel 3d-Cry toxins and obtain sequences of specific domains for further comprehensive in silico experiments in constructing artificial toxins.

ACS Style

Anton E. Shikov; Yury V. Malovichko; Rostislav K. Skitchenko; Anton A. Nizhnikov; Kirill S. Antonets. No More Tears: Mining Sequencing Data for Novel Bt Cry Toxins with CryProcessor. Toxins 2020, 12, 204 .

AMA Style

Anton E. Shikov, Yury V. Malovichko, Rostislav K. Skitchenko, Anton A. Nizhnikov, Kirill S. Antonets. No More Tears: Mining Sequencing Data for Novel Bt Cry Toxins with CryProcessor. Toxins. 2020; 12 (3):204.

Chicago/Turabian Style

Anton E. Shikov; Yury V. Malovichko; Rostislav K. Skitchenko; Anton A. Nizhnikov; Kirill S. Antonets. 2020. "No More Tears: Mining Sequencing Data for Novel Bt Cry Toxins with CryProcessor." Toxins 12, no. 3: 204.

Journal article
Published: 05 February 2020 in Bioinformatics
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Motivation Halides are negatively charged ions of halogens, forming fluorides (F−), chlorides (Cl−), bromides (Br−) and iodides (I−). These anions are quite reactive and interact both specifically and non-specifically with proteins. Despite their ubiquitous presence and important roles in protein function, little is known about the preferences of halides binding to proteins. To address this problem, we performed the analysis of halide–protein interactions, based on the entries in the Protein Data Bank. Results We have compiled a pipeline for the quick analysis of halide-binding sites in proteins using the available software. Our analysis revealed that all of halides are strongly attracted by the guanidinium moiety of arginine side chains, however, there are also certain preferences among halides for other partners. Furthermore, there is a certain preference for coordination numbers in the binding sites, with a correlation between coordination numbers and amino acid composition. This pipeline can be used as a tool for the analysis of specific halide–protein interactions and assist phasing experiments relying on halides as anomalous scatters. Availability and implementation All data described in this article can be reproduced via complied pipeline published at https://github.com/rostkick/Halide_sites/blob/master/README.md. Supplementary information Supplementary data are available at Bioinformatics online.

ACS Style

Rostislav K Skitchenko; Dmitrii Usoltsev; Mayya Uspenskaya; Andrey V Kajava; Albert Guskov. Census of halide-binding sites in protein structures. Bioinformatics 2020, 36, 3064 -3071.

AMA Style

Rostislav K Skitchenko, Dmitrii Usoltsev, Mayya Uspenskaya, Andrey V Kajava, Albert Guskov. Census of halide-binding sites in protein structures. Bioinformatics. 2020; 36 (10):3064-3071.

Chicago/Turabian Style

Rostislav K Skitchenko; Dmitrii Usoltsev; Mayya Uspenskaya; Andrey V Kajava; Albert Guskov. 2020. "Census of halide-binding sites in protein structures." Bioinformatics 36, no. 10: 3064-3071.

Journal article
Published: 23 January 2020 in Scientific Reports
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Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.

ACS Style

Anton Shikov; Rostislav K. Skitchenko; Alexander V. Predeus; Yury A. Barbitoff. Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits. Scientific Reports 2020, 10, 1 -10.

AMA Style

Anton Shikov, Rostislav K. Skitchenko, Alexander V. Predeus, Yury A. Barbitoff. Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits. Scientific Reports. 2020; 10 (1):1-10.

Chicago/Turabian Style

Anton Shikov; Rostislav K. Skitchenko; Alexander V. Predeus; Yury A. Barbitoff. 2020. "Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits." Scientific Reports 10, no. 1: 1-10.

Research paper
Published: 01 January 2020 in Prion
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Semi-denaturing detergent agarose gel electrophoresis (SDD-AGE) was proposed by Vitaly V. Kushnirov in the Michael D. Ter-Avanesyan’s laboratory as a method to compare sizes of amyloid aggregates. Currently, this method is widely used for amyloid investigation, but mostly as a qualitative approach. In this work, we assessed the possibilities and limitations of the quantitative analysis of amyloid aggregate size distribution using SDD-AGE results. For this purpose, we used aggregates of two well-characterized yeast amyloid-forming proteins, Sup35 and Rnq1, and developed a protocol to standardize image analysis and process the result. A detailed investigation of factors that may affect the results of SDD-AGE revealed that both the cell lysis method and electrophoresis conditions can substantially affect the estimation of aggregate size. Despite this, quantitative analysis of SDD-AGE results is possible when one needs to estimate and compare the size of aggregates on the same gel, or even in different experiments, if the experimental conditions are tightly controlled and additional standards are used.

ACS Style

Polina B. Drozdova; Yury A. Barbitoff; Mikhail V. Belousov; Rostislav K. Skitchenko; Tatyana M. Rogoza; Jeremy Y. Leclercq; Andrey V. Kajava; Andrew G. Matveenko; Galina A. Zhouravleva; Stanislav A. Bondarev. Estimation of amyloid aggregate sizes with semi-denaturing detergent agarose gel electrophoresis and its limitations. Prion 2020, 14, 118 -128.

AMA Style

Polina B. Drozdova, Yury A. Barbitoff, Mikhail V. Belousov, Rostislav K. Skitchenko, Tatyana M. Rogoza, Jeremy Y. Leclercq, Andrey V. Kajava, Andrew G. Matveenko, Galina A. Zhouravleva, Stanislav A. Bondarev. Estimation of amyloid aggregate sizes with semi-denaturing detergent agarose gel electrophoresis and its limitations. Prion. 2020; 14 (1):118-128.

Chicago/Turabian Style

Polina B. Drozdova; Yury A. Barbitoff; Mikhail V. Belousov; Rostislav K. Skitchenko; Tatyana M. Rogoza; Jeremy Y. Leclercq; Andrey V. Kajava; Andrew G. Matveenko; Galina A. Zhouravleva; Stanislav A. Bondarev. 2020. "Estimation of amyloid aggregate sizes with semi-denaturing detergent agarose gel electrophoresis and its limitations." Prion 14, no. 1: 118-128.

Journal article
Published: 16 October 2019 in Molecular Medicine Reports
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The present study reports on the frequency and the spectrum of genetic variants causative of monogenic diabetes in Russian children with non‑type 1 diabetes mellitus. The present study included 60 unrelated Russian children with non‑type 1 diabetes mellitus diagnosed before the age of 18 years. Genetic variants were screened using whole‑exome sequencing (WES) in a panel of 35 genes causative of maturity onset diabetes of the young (MODY) and transient or permanent neonatal diabetes. Verification of the WES results was performed using PCR‑direct sequencing. A total of 38 genetic variants were identified in 33 out of 60 patients (55%). The majority of patients (27/33, 81.8%) had variants in MODY‑related genes: GCK (n=19), HNF1A (n=2), PAX4 (n=1), ABCC8 (n=1), KCNJ11 (n=1), GCK+HNF1A (n=1), GCK+BLK (n=1) and GCK+BLK+WFS1 (n=1). A total of 6 patients (6/33, 18.2%) had variants in MODY‑unrelated genes: GATA6 (n=1), WFS1 (n=3), EIF2AK3 (n=1) and SLC19A2 (n=1). A total of 15 out of 38 variants were novel, including GCK, HNF1A, BLK, WFS1, EIF2AK3 and SLC19A2. To summarize, the present study demonstrates a high frequency and a wide spectrum of genetic variants causative of monogenic diabetes in Russian children with non‑type 1 diabetes mellitus. The spectrum includes previously known and novel variants in MODY‑related and unrelated genes, with multiple variants in a number of patients. The prevalence of GCK variants indicates that diagnostics of monogenic diabetes in Russian children may begin with testing for MODY2. However, the remaining variants are present at low frequencies in 9 different genes, altogether amounting to ~50% of the cases and highlighting the efficiency of using WES in non‑GCK‑MODY cases.

ACS Style

Oleg S. Glotov; Elena A. Serebryakova; Mariia E. Turkunova; Olga Efimova; Andrey S. Glotov; Yury Barbitoff; Yulia Nasykhova; Alexander Predeus; Dmitrii E. Polev; Mikhail Fedyakov; Irina V. Polyakova; Tatyana E. Ivashchenko; Natalia Y. Shved; Elena S. Shabanova; Alena Tiselko; Olga V. Romanova; Andrey M. Sarana; Anna A. Pendina; Sergey G. Scherbak; Ekaterina V. Musina; Anastasiia V. Petrovskaia‑Kaminskaia; Liubov R. Lonishin; Liliya V. Ditkovskaya; Liudmila А. Zhelenina; Ludmila V. Tyrtova; Olga S. Berseneva; Rostislav Skitchenko; Evgeny Suspitsin; Elena B. Bashnina; Vladislav Baranov. Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes. Molecular Medicine Reports 2019, 20, 4905 -4914.

AMA Style

Oleg S. Glotov, Elena A. Serebryakova, Mariia E. Turkunova, Olga Efimova, Andrey S. Glotov, Yury Barbitoff, Yulia Nasykhova, Alexander Predeus, Dmitrii E. Polev, Mikhail Fedyakov, Irina V. Polyakova, Tatyana E. Ivashchenko, Natalia Y. Shved, Elena S. Shabanova, Alena Tiselko, Olga V. Romanova, Andrey M. Sarana, Anna A. Pendina, Sergey G. Scherbak, Ekaterina V. Musina, Anastasiia V. Petrovskaia‑Kaminskaia, Liubov R. Lonishin, Liliya V. Ditkovskaya, Liudmila А. Zhelenina, Ludmila V. Tyrtova, Olga S. Berseneva, Rostislav Skitchenko, Evgeny Suspitsin, Elena B. Bashnina, Vladislav Baranov. Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes. Molecular Medicine Reports. 2019; 20 (6):4905-4914.

Chicago/Turabian Style

Oleg S. Glotov; Elena A. Serebryakova; Mariia E. Turkunova; Olga Efimova; Andrey S. Glotov; Yury Barbitoff; Yulia Nasykhova; Alexander Predeus; Dmitrii E. Polev; Mikhail Fedyakov; Irina V. Polyakova; Tatyana E. Ivashchenko; Natalia Y. Shved; Elena S. Shabanova; Alena Tiselko; Olga V. Romanova; Andrey M. Sarana; Anna A. Pendina; Sergey G. Scherbak; Ekaterina V. Musina; Anastasiia V. Petrovskaia‑Kaminskaia; Liubov R. Lonishin; Liliya V. Ditkovskaya; Liudmila А. Zhelenina; Ludmila V. Tyrtova; Olga S. Berseneva; Rostislav Skitchenko; Evgeny Suspitsin; Elena B. Bashnina; Vladislav Baranov. 2019. "Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes." Molecular Medicine Reports 20, no. 6: 4905-4914.

Original article
Published: 03 September 2019 in Molecular Genetics & Genomic Medicine
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Background Allele frequency data from large exome and genome aggregation projects such as the Genome Aggregation Database (gnomAD) are of ultimate importance to the interpretation of medical resequencing data. However, allele frequencies might significantly differ in poorly studied populations that are underrepresented in large‐scale projects, such as the Russian population. Methods In this work, we leveraged our access to a large dataset of 694 exome samples to analyze genetic variation in the Northwest Russia. We compared the spectrum of genetic variants to the dbSNP build 151, and made estimates of ClinVar‐based autosomal recessive (AR) disease allele prevalence as compared to gnomAD r. 2.1. Results An estimated 9.3% of discovered variants were not present in dbSNP. We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers‐Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies. We also make primary estimates of monogenic disease incidence in the population, with retinal dystrophy, cystic fibrosis, and phenylketonuria being the most frequent AR pathologies. Conclusion Our observations demonstrate the utility of population‐specific allele frequency data to the diagnosis of monogenic disorders using high‐throughput technologies.

ACS Style

Yury A. Barbitoff; Rostislav Skitchenko; Olga I. Poleshchuk; Anton E. Shikov; Elena A. Serebryakova; Yulia Nasykhova; Dmitrii E. Polev; Anna R. Shuvalova; Irina V. Shcherbakova; Mikhail Fedyakov; Oleg S. Glotov; Andrey S. Glotov; Alexander V. Predeus. Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia. Molecular Genetics & Genomic Medicine 2019, 7, e964 .

AMA Style

Yury A. Barbitoff, Rostislav Skitchenko, Olga I. Poleshchuk, Anton E. Shikov, Elena A. Serebryakova, Yulia Nasykhova, Dmitrii E. Polev, Anna R. Shuvalova, Irina V. Shcherbakova, Mikhail Fedyakov, Oleg S. Glotov, Andrey S. Glotov, Alexander V. Predeus. Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia. Molecular Genetics & Genomic Medicine. 2019; 7 (11):e964.

Chicago/Turabian Style

Yury A. Barbitoff; Rostislav Skitchenko; Olga I. Poleshchuk; Anton E. Shikov; Elena A. Serebryakova; Yulia Nasykhova; Dmitrii E. Polev; Anna R. Shuvalova; Irina V. Shcherbakova; Mikhail Fedyakov; Oleg S. Glotov; Andrey S. Glotov; Alexander V. Predeus. 2019. "Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia." Molecular Genetics & Genomic Medicine 7, no. 11: e964.