Identification of Novel Genes Associated to Major Mental Disease by Whole Exome Sequencing in Families with High Prevalence

2017 ◽  
Vol 41 (S1) ◽  
pp. S98-S99
Author(s):  
J. Pol Fuster ◽  
L. Ruiz Guerra ◽  
B. Ortega Vila ◽  
A. Medina Dols ◽  
B. Bisbal Carrió ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Mental Disease ◽  
Psychotic Symptoms ◽  
Disease Etiology ◽  
New Genes ◽  
Whole Exome ◽  
High Prevalence ◽  
Rare Genetic Variants

IntroductionThe identification of new genetic variants underlying psychosis is crucial to improve its molecular diagnosis and to determine the disease etiology, which is necessary to develop new therapeutic targets.AimTo identify novel rare genetic variants associated to mental disorders, using whole exome sequencing (WES).MethodsTwo families with high prevalence of mental disease were genotyped using WES. The first family has 5 members affected, the mother with a bipolar disorder, three sons, two with schizophrenia and one with schizoaffective disorder, and a cousin with major depression and psychotic symptoms. The second family is constituted by 38 members affected by major mental diseases in three generations. Key affected members of each family were genotyped by WES. Shared rare variants, with allelic frequencies below 0.5% in general population, were identified among the affected members of the family. The segregation of those variants was confirmed by Sanger sequencing.ResultsIn family 1, thirty-seven genetic variants related to neurodevelopment were identified. Two of those variants in the genes TRIP12 and RNF25 segregated with psychosis. In family 2, seven rare genetic variants contained in genes related to neurodevelopment were identified. A mutation in the gene ARHGAP19 segregated with psychosis.ConclusionsThree new genes have been found to be associated with psychosis. TRIP12 and RNF25 encode two E3-ubiquitin ligases which modulate the Wnt pathway, mutations in which lead to neurodevelopmental defects. ARHGAP19 encodes a GTPase which regulates the RhoA protein, involved in the regulation of the cytoskeleton.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

2015 ◽  
Vol 13 (S1) ◽  
Author(s):  
E Sanchez ◽  
S Grandemange ◽  
F Tran Mau-Them ◽  
P Louis-Plence ◽  
A Carbasse ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Whole Exome ◽  
Rare Genetic Variants

scholarly journals Analysis workflow to assess de novo genetic variants from human whole-exome sequencing

2021 ◽  
Vol 2 (1) ◽  
pp. 100383
Author(s):  
Nicholas S. Diab ◽  
Spencer King ◽  
Weilai Dong ◽  
Garrett Allington ◽  
Amar Sheth ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
De Novo ◽  
Whole Exome ◽  
Analysis Workflow

scholarly journals Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Semyon Kolmykov ◽  
Gennady Vasiliev ◽  
Ludmila Osadchuk ◽  
Maxim Kleschev ◽  
Alexander Osadchuk
Keyword(s):  
Exome Sequencing ◽  
Ethnic Groups ◽  
Whole Exome Sequencing ◽  
Complex Traits ◽  
Semen Quality ◽  
Population Sample ◽  
Sperm Concentration ◽  
Sequencing Analysis ◽  
New Genes ◽  
Whole Exome

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.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Haematologica ◽  
2016 ◽  
Vol 101 (10) ◽  
pp. 1170-1179 ◽  
Author(s):  
B. Johnson ◽  
G. C. Lowe ◽  
J. Futterer ◽  
M. Lordkipanidze ◽  
D. MacDonald ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Whole Exome ◽  
Inherited Thrombocytopenia

scholarly journals Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

2018 ◽  
Author(s):  
Youngha Lee ◽  
Jin Sook Lee ◽  
Soo Yeon Kim ◽  
Jaeso Cho ◽  
Yongjin Yoo ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Neurodevelopmental Disorders ◽  
Pediatric Patients ◽  
Medical System ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants

AbstractImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).ObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.Design, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Children’s Hospital.ExposuresWES of patients and parents and subsequent evaluation of genetic variants.Main outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.ResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.Conclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.Key pointsQuestionWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?FindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.MeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

Identification of novel and rare recurrent genetic variants in early onset chronic pancreatitis by whole exome sequencing

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S20
Author(s):  
Agnieszka Rygiel ◽  
Grzegorz Oracz ◽  
Tomasz Gambin ◽  
Elwira Kołodziejczyk ◽  
Joanna Kosinska ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Early Onset ◽  
Whole Exome
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