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 Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies

2016 ◽  
Vol 23 (2) ◽  
pp. 73-85
Author(s):  
Eglė Preikšaitienė ◽  
Laima Ambrozaitytė ◽  
Živilė Maldžienė ◽  
Aušra Morkūnienė ◽  
Loreta Cimbalistienė ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Single Gene ◽  
Genetic Alterations ◽  
Sequence Variants ◽  
Candidate Sequence ◽  
Genetic Causes ◽  
Genome Wide ◽  
Whole Exome

Background. Intellectual disability affects about 1–2% of the general population worldwide, and this is the leading socio-economic problem of health care. The evaluation of the genetic causes of intellectual disability is challenging because these conditions are genetically heterogeneous with many different genetic alterations resulting in clinically indistinguishable phenotypes. Genome wide molecular technologies are effective in a research setting for establishing the new genetic basis of a disease. We describe the first Lithuanian experience in genome-wide CNV detection and whole exome sequencing, presenting the results obtained in the research project UNIGENE.Materials and methods. The patients with developmental delay/intellectual disability have been investigated (n = 66). Diagnostic screening was performed using array-CGH technology. FISH and real time-PCR were used for the confirmation of gene-dose imbalances and investigation of parental samples. Whole exome sequencing using the next generation high throughput NGS technique was used to sequence the samples of 12 selected families.Results. 14 out of 66 patients had pathogenic copy number variants, and one patient had novel likely pathogenic aberration (microdeletion at 4p15.2). Twelve families have been processed for whole exome sequencing. Two identified sequence variants could be classified as pathogenic (in MECP2, CREBBP genes). The other families had several candidate intellectual disability gene variants that are of unclear clinical significance and must be further investigated for possible effect on the molecular pathways of intellectual disability.Conclusions. The genetic heterogeneity of intellectual disability requires genome wide approaches, including detection of chromosomal aberrations by chromosomal microarrays and whole exome sequencing capable of uncovering single gene mutations. This study demonstrates the  benefits and challenges that accompany the use of genome wide molecular technologies and provides genotype-phenotype information on 32 patients with chromosomal imbalances and ID candidate sequence variants.

Exploration of the role of whole exome sequencing variants in -associated Parkinson disease

2021 ◽  
Vol 132 (2) ◽  
pp. S113
Author(s):  
Elizabeth Geena Woo ◽  
Frank Donovan ◽  
Barbara Stubblefield ◽  
Settara Chandrasekharappa ◽  
Grisel Lopez ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

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

scholarly journals A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chiara Fabbri ◽  
Siegfried Kasper ◽  
Alexander Kautzky ◽  
Joseph Zohar ◽  
Daniel Souery ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Genome Wide ◽  
Whole Exome ◽  
Resistant Depression

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

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