The Pioneer Advantage: Filling the blank spots on the map of genome diversity in Europe

Oleksyk, Tarás K.; Wolfsberger, Walter; Schubelka, Khrystyna; Mangul, Serghei; O’Brien, Stephen J.

doi:10.1093/gigascience/giac081

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…This is mainly due to only the recent availability of NGSbased diagnostic tests. Also, the whole-genome data on the general genetic composition of the population has just been published recently [8,16,17], there was a need to use genome data available to evaluate the diagnostic yield of WES and NGS gene panel.…”

Section: Discussionmentioning

confidence: 99%

“…Apart of isolated case reports, there has not been a comprehensive study on genetic causes of GDD/ID conducted in Ukraine, in particular, on diagnostic yield of NGS panels and WES techniques. This report will help pave the way to detecting locally significant candidate pathogenic variants for future variant resolution and familial studies in Ukraine and across Eastern Europe [8].…”

Section: Introductionmentioning

confidence: 92%

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Genetic determinants of global developmental delay and intellectual disability in Ukrainian children

Shchubelka,

Turova,

Wolfsberger

et al. 2024

J Neurodevelop Disord

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Background Global developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abnormalities. Next-generation sequencing (NGS) techniques have improved the identification of pathogenic variants and genes related to developmental delay. This study aimed to evaluate the yield of whole exome sequencing (WES) and neurodevelopmental disorder gene panel sequencing in a pediatric cohort from Ukraine. Additionally, the study computationally predicted the effect of variants of uncertain significance (VUS) based on recently published genetic data from the country’s healthy population. Methods The study retrospectively analyzed WES or gene panel sequencing findings of 417 children with global developmental delay, intellectual disability, and/or other symptoms. Variants of uncertain significance were annotated using CADD-Phred and SIFT prediction scores, and their frequency in the healthy population of Ukraine was estimated. Results A definitive molecular diagnosis was established in 66 (15.8%) of the individuals. WES diagnosed 22 out of 37 cases (59.4%), while the neurodevelopmental gene panel identified 44 definitive diagnoses among the 380 tested patients (12.1%). Non-diagnostic findings (VUS and carrier) were reported in 350 (83.2%) individuals. The most frequently diagnosed conditions were developmental and epileptic encephalopathies associated with severe epilepsy and GDD/ID (associated genes ARX, CDKL5, STXBP1, KCNQ2, SCN2A, KCNT1, KCNA2). Additionally, we annotated 221 VUS classified as potentially damaging, AD or X-linked, potentially increasing the diagnostic yield by 30%, but 18 of these variants were present in the healthy population of Ukraine. Conclusions This is the first comprehensive study on genetic causes of GDD/ID conducted in Ukraine. This study provides the first comprehensive investigation of the genetic causes of GDD/ID in Ukraine. It presents a substantial dataset of diagnosed genetic conditions associated with GDD/ID. The results support the utilization of NGS gene panels and WES as first-line diagnostic tools for GDD/ID cases, particularly in resource-limited settings. A comprehensive approach to resolving VUS, including computational effect prediction, population frequency analysis, and phenotype assessment, can aid in further reclassification of deleterious VUS and guide further testing in families.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Genetic determinants of global developmental delay and intellectual disability in Ukrainian children

Shchubelka,

Turova,

Wolfsberger

et al. 2024

J Neurodevelop Disord

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“…The Carpathian Mountains region in Eastern Europe including Ukraine’s Transcarpathia and Romania’s Satu Mare and Baia Mare provinces, has been under-researched in terms of population genomics despite its rich history and ethnic diversity (Oleksyk et al, 2022). The region’s socio-economic reliance on agriculture and lower levels of industrialization compared to other areas in Ukraine and Romanian provides potential for important genomic discoveries.…”

Section: Contextmentioning

confidence: 99%

ROUA Database: 300 Human Genomes from the border of Ukraine and Romania

Shchubelka,

Wolfsberger,

Oleksyk

et al. 2024

Preprint

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We present a multi-layered data source (ROUA Database) providing the results of Whole Genome Sequencing of two human populations in the Carpathian Mountains region, specifically Ukraine’s Transcarpathia and Romania’s Satu Mare and Baia Mare provinces, areas previously underexplored in population genomics. The database contains the raw and annotated files of the whole genome sequences from 300 individuals from these regions, including annotations of common and unique genetic variants following a sampling protocol designed to capture the genetic diversity of Ukrainians and Romanians, including minority groups like Wallachians and Roma. The data is hosted on a dedicated web resource. We provide information on how to access to results of primary and secondary analysis of the data, including comparative analysis with previously published populations from Ukraine, and populations from International Genome Sample Resource and Human Genome Diversity Project. The free research access to this database is contributing to growing understanding of human genetic diversity in Central Europe. This effort emphasizes the potential for reuse of the generated data, advocating for open access to support future research in genomics, bioinformatics, and personalized medicine.

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“…Although there are a great many studies investigating the impact of pathogenic mutations in different cancers cohorts, yet the predisposing germline deleterious mutations for cancers in healthy populations have not been investigated so far. In this study, taking advantage of the publicly available genome-wide mutational database of global populations, such as the Exome Aggregation Consortium (ExAC) [ 36 , 37 ] and Human Genome Diversity Project (HGDP) [ 38 ], we used in an in silico approach to analyze highly deleterious mutated kinases throughout the human kinome relevant to carcinogenesis. The aim of our study is to identify the predisposing pathogenic kinase variants which are likely to be involved in cancer development in global populations.…”

Section: Introductionmentioning

confidence: 99%

Predisposing deleterious variants in the cancer-associated human kinases in the global populations

Khan,

Anwar,

Gohar

et al. 2024

PLoS ONE

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Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.

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The Pioneer Advantage: Filling the blank spots on the map of genome diversity in Europe

Cited by 8 publications

References 35 publications

Genetic determinants of global developmental delay and intellectual disability in Ukrainian children

Genetic determinants of global developmental delay and intellectual disability in Ukrainian children

ROUA Database: 300 Human Genomes from the border of Ukraine and Romania

Predisposing deleterious variants in the cancer-associated human kinases in the global populations

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