scholarly journals Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family

2018 ◽  
Vol 25 (7) ◽  
pp. 909-917 ◽  
Author(s):  
Julia Y Mescheriakova ◽  
Annemieke JMH Verkerk ◽  
Najaf Amin ◽  
André G Uitterlinden ◽  
Cornelia M van Duijn ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Rare Variants ◽  
Missense Variant ◽  
Joint Effect ◽  
Genome Wide ◽  
Whole Exome ◽  
Coding Variants

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. Methods: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. Results: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). Conclusion: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.

TSC22D2 identified as a candidate susceptibility gene of multi-cancer pedigree using genome-wide linkage analysis and whole-exome sequencing

2019 ◽  
Vol 40 (7) ◽  
pp. 819-827 ◽  
Author(s):  
Lan Xiao ◽  
Fang Wei ◽  
Fang Liang ◽  
Qiao Li ◽  
Hao Deng ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Transforming Growth Factor ◽  
Susceptibility Gene ◽  
Snp Array ◽  
Multiple Tumor ◽  
Genome Wide ◽  
Whole Exome

AbstractCancer is a complex disease, which may involve multiple tumor susceptibility genes that mediate the occurrence and development of tumor molecular events. This study aimed to identify new genetic loci using genome-wide linkage analysis and whole-exome sequencing in a rare, large multi-cancer pedigree recently found in China. We performed high-throughput single-nucleotide polymorphism (SNP) array and linkage analyses of 24 core members of this pedigree and found that the disease susceptibility locus in the multi-cancer pedigree was mapped to chromosome 3q24-26. We also used microsatellites to further validate the results of the SNP locus linkage analysis. Furthermore, we sequenced the whole exome of three members in this pedigree and identified a novel mutant of transforming growth factor β stimulated clone 22 domain family, member 2 (TSC22D2, c.-91T-C) cosegregated with the cancer phenotype. This change was at a highly conserved position, and the exome results were validated using linkage analysis. Moreover, we found the histone H4 transcription factor (HINFP) binds to the promoter region of TSC22D2 and may regulate its transcription. In conclusion, our findings are of great significance to the early pathogenesis of tumors and contribute to the search for molecular targets for the early prevention and treatment of tumors.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

scholarly journals Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sara Konstantin Nissen ◽  
Mette Christiansen ◽  
Marie Helleberg ◽  
Kathrine Kjær ◽  
Sofie Eg Jørgensen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Signaling Molecules ◽  
Innate Immune ◽  
Whole Exome ◽  
Genes Encoding ◽  
Hiv 1

scholarly journals Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

2017 ◽  
Vol 3 (5) ◽  
pp. e177 ◽  
Author(s):  
Javier Ruiz-Martínez ◽  
Luis J. Azcona ◽  
Alberto Bergareche ◽  
Jose F. Martí-Massó ◽  
Coro Paisán-Ruiz
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Wide Association Study ◽  
Single Gene ◽  
Gene Mutations ◽  
Complement Control Protein ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

scholarly journals A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

2017 ◽  
Vol 176 (5) ◽  
pp. K9-K14 ◽  
Author(s):  
Sandrine Caburet ◽  
Ronit Beck Fruchter ◽  
Bérangère Legois ◽  
Marc Fellous ◽  
Stavit Shalev ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Polycystic Ovary ◽  
Missense Variant ◽  
Genetic Alterations ◽  
Homozygous Mutation ◽  
Gonadotropin Secretion ◽  
Whole Exome ◽  
A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

scholarly journals Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays

2017 ◽  
Vol 107 (2) ◽  
pp. 457-466.e9 ◽  
Author(s):  
Svetlana A. Yatsenko ◽  
Priya Mittal ◽  
Michelle A. Wood-Trageser ◽  
Mirka W. Jones ◽  
Urvashi Surti ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Uterine Leiomyomas ◽  
Genome Wide ◽  
Whole Exome ◽  
Genomic Landscape

Abstract MP08: Whole Exome Sequencing Study Identified A Novel Variant For Kidney Function And Progression Of Chronic Kidney Disease

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Changwei Li ◽  
Michael Francis ◽  
Adrianna Westbrook ◽  
Ruiyuan Zhang ◽  
Ye Shen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Kidney Function ◽  
Cystatin C ◽  
Smoking Status ◽  
Missense Variant ◽  
Ckd Progression ◽  
Whole Exome

Introduction: Most genetic variants for chronic kidney disease (CKD) have been identified in non-coding regions, with functional roles that are difficult to interpret. Hypothesis: A whole exome sequencing study focusing on coding variants will reveal novel mechanisms of kidney function and CKD. Methods: We performed whole exome sequencing analyses of cystatin C among 29,789 UK Biobank (UKB) participants with further confirmation among 4,297 white and 607 African American participants of the Health and Retirement Study (HRS). Conditional analyses for loci achieving exome-wide significance ( P <3.5х10 -7 ) were conducted in UKB using both the exome (n=29,789) and imputed GWAS data (n=295,122). Genomic findings were tested for relevance to baseline estimated glomerular filtration rate (eGFR) and stringently adjudicated CKD progression events among participants of the Chronic Renal Insufficiency Cohort (CRIC) by race and smoking status, using a base model and a full model ( Table ). Results: We identified a common missense variant, CST9 rs2983640, in a previously reported locus ( CST3 intron rs13038305), of which the minor G allele was associated with lower serum cystatin C level (UKB: beta=-0.03 mg/L, P =7.64х10 -92 ; HRS whites: beta=-0.05 mg/L, P =4.71х10 -6 ; HRS African Americans: beta=-0.03 mg/L, P =0.64; and multi-ethnic meta-analysis beta=-0.03 mg/L, P =2.46х10 -91 ). After controlling for the CST3 variant, the G allele was associated with higher cystatin C level (UKB exome: beta=0.003 mg/L, P =0.04; UKB GWAS: beta=0.003 mg/L, P =1.47х10 -10 ). Similar associations were identified in white CRIC participants (direct effect: beta=-0.05 mg/L, P =0.005; conditional effect: beta=0.004 mg/L, P =0.86). The CST9 rs2983640 G allele was associated with lower baseline eGFR (base model beta=-0.33 ml/min/1.73 m 2 , P =1.98х10 -6 ) and higher hazard of developing CKD progression independent of the reported CST3 variant ( Table ). Conclusions: We identified a novel missense variant influencing cystatin C level and CKD progression.

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