Dataset Information

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.

ABSTRACT: 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.

SUBMITTER: Glotov OS

PROVIDER: S-EPMC6854535 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Glotov Oleg S OS Serebryakova Elena A EA Turkunova Mariia E ME Efimova Olga A OA Glotov Andrey S AS Barbitoff Yury A YA Nasykhova Yulia A YA Predeus Alexander V AV Polev Dmitrii E DE Fedyakov Mikhail A MA Polyakova Irina V IV Ivashchenko Tatyana E TE Shved Natalia Y NY Shabanova Elena S ES Tiselko Alena V AV Romanova Olga V OV Sarana Andrey M AM Pendina Anna A AA Scherbak Sergey G SG Musina Ekaterina V EV Petrovskaia-Kaminskaia Anastasiia V AV Lonishin Liubov R LR Ditkovskaya Liliya V LV Zhelenina Liudmila А LА Tyrtova Ludmila V LV Berseneva Olga S OS Skitchenko Rostislav K RK Suspitsin Evgenii N EN Bashnina Elena B EB Baranov Vladislav S VS

Molecular medicine reports 20191016 6

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 ...[more]

PMID: 31638168

Similar Datasets

Project description:The global trend toward the reduction of human spermatogenic function observed in many countries, including Russia, raised the problem of extensive screening and monitoring of male fertility and elucidation of its genetic and ethnic mechanisms. Recently, whole-exome sequencing (WES) was developed as a powerful tool for genetic analysis of complex traits. We present here the first Russian WES study for identification of new genes associated with semen quality. The experimental 3 × 2 design of the WES study was based on the analysis of 157 samples including three ethnic groups-Slavs (59), Buryats (n = 49), and Yakuts (n = 49), and two different semen quality groups-pathozoospermia (n = 95) and normospermia (n = 62). Additionally, our WES study group was negative for complete AZF microdeletions of the Y-chromosome. The normospermia group included men with normal sperm parameters in accordance with the WHO-recommended reference limit. The pathozoospermia group included men with impaired semen quality, namely, with any combined parameters of sperm concentration <15 × 106/ml, and/or progressive motility <32%, and/or normal morphology <4%. The WES was performed for all 157 samples. Subsequent calling and filtering of variants were carried out according to the GATK Best Practices recommendations. On the genotyping stage, the samples were combined into four cohorts: three sets corresponded to three ethnic groups, and the fourth set contained all the 157 whole-exome samples. Association of the obtained polymorphisms with semen quality parameters was investigated using the χ2 test. To prioritize the obtained variants associated with pathozoospermia, their effects were determined using Ensembl Variant Effect Predictor. Moreover, polymorphisms located in genes expressed in the testis were revealed based on the genomic annotation. As a result, the nine potential SNP markers rs6971091, rs557806, rs610308, rs556052, rs1289658, rs278981, rs1129172, rs12268007, and rs17228441 were selected for subsequent verification on our previously collected population sample (about 1,500 males). The selected variants located in seven genes FAM71F1, PPP1R15A, TRIM45, PRAME, RBM47, WDFY4, and FSIP2 that are expressed in the testis and play an important role in cell proliferation, meiosis, and apoptosis.

Project description:Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5' UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-?B signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.

Project description:BackgroundDystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.MethodsFor this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.FindingsWe sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.InterpretationIn this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.FundingElse Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets