scholarly journals Analysis of common and rare VPS13C variants in late onset Parkinson disease

2019 ◽  
Author(s):  
Uladzislau Rudakou ◽  
Jennifer A. Ruskey ◽  
Lynne Krohn ◽  
Sandra B. Laurent ◽  
Dan Spiegelman ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Late Onset ◽  
Meta Analysis ◽  
Compound Heterozygous ◽  
Tagging Snp ◽  
Targeted Next Generation Sequencing ◽  
Functional Studies ◽  
Compound Heterozygous Variants ◽  
Reduced Risk

AbstractObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 PD patients and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo bi-allelic carriers of rare VPS13C variants were found among patients and two carriers of compound heterozygous variants were found in two controls. There was no statistically significant burden of rare (MAF<1%) or very rare (MAF<0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V (OR=0.48, 95%CI=0.28-0.82, p=0.0052). This haplotype was not in linkage disequilibrium (LD) with the known genome-wide association study (GWAS) top hit.ConclusionsOur results do not support a role for rare heterozygous or bi-allelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

scholarly journals Analysis of common and rare VPS13C variants in late-onset Parkinson disease

2020 ◽  
Vol 6 (1) ◽  
pp. 385 ◽  
Author(s):  
Uladzislau Rudakou ◽  
Jennifer A. Ruskey ◽  
Lynne Krohn ◽  
Sandra B. Laurent ◽  
Dan Spiegelman ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Meta Analysis ◽  
Compound Heterozygous ◽  
Tagging Snp ◽  
Targeted Next Generation Sequencing ◽  
Compound Heterozygous Variants ◽  
Reduced Risk

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.ConclusionsOur results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

scholarly journals A novel LOXHD1 variant in a Chinese couple with hearing loss

2019 ◽  
Vol 47 (12) ◽  
pp. 6082-6090 ◽  
Author(s):  
Chuan Zhang ◽  
Shengju Hao ◽  
Yali Liu ◽  
Bingbo Zhou ◽  
Furong Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Diagnosis ◽  
Protein Function ◽  
Mexican American ◽  
Compound Heterozygous ◽  
Congenital Hearing Loss ◽  
Targeted Next Generation Sequencing ◽  
Novel Variants ◽  
Novel Variant ◽  
Compound Heterozygous Variants

Objective To perform molecular diagnosis and genetic counseling in a young Chinese couple with congenital hearing loss. Methods Variant screening analysis was performed by PCR and direct Sanger sequencing or targeted next-generation sequencing of all known hearing loss genes. Novel variants were evaluated by PolyPhen2 and PROVEAN software tools to evaluate possible effects on protein function. Results We identified causative variants in the young couple: c.235delC (rs80338943)/c.299-300delAT (rs111033204) compound heterozygous variants of GJB2 in the husband and c.1828G>A (p.Glu610Lys, rs535637788)/c.2825-2827delAGA compound heterozygous variants of LOXHD1 in the wife. The LOXHD1 c.1828G>A variant has only previously been reported in a Mexican-American individual in the 1000 Genomes Project database. Using PolyPhen2 and PROVEAN, we speculated that the LOXHD1 variant c.1828G>A is potentially pathogenic. Conclusion We carried out molecular diagnosis in a young couple with congenital hearing loss, and identified different disease-causing genes in the two individuals. The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. We determined this to be a potential pathogenic variant, and a novel variant associated with hearing loss in a Chinese individual.

scholarly journals Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

2019 ◽  
Author(s):  
Hanna Helgeland ◽  
Marte Sodeland ◽  
Nina Zoric ◽  
Jacob Seilø Torgersen ◽  
Fabian Grammes ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Beta Carotene ◽  
Color Variation ◽  
Flesh Color ◽  
Functional Studies ◽  
Genetic Components ◽  
Genome Wide ◽  
A Genome ◽  
Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL-region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, several functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

scholarly journals Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Evelina Siavrienė ◽  
Gunda Petraitytė ◽  
Birutė Burnytė ◽  
Aušra Morkūnienė ◽  
Violeta Mikštienė ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Recessive ◽  
Premature Termination Codon ◽  
Limb Girdle Muscular Dystrophy ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Targeted Next Generation Sequencing ◽  
Splicing Variant ◽  
Cdna Analysis ◽  
Compound Heterozygous Variants

Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.

Lactoferrin Supplementation to Prevent Late-Onset Sepsis in Preterm Infants: A Meta-Analysis

2019 ◽  
Author(s):  
Abdul Razak ◽  
Asif Hussain
Keyword(s):  
Preterm Infants ◽  
Web Of Science ◽  
Late Onset ◽  
Meta Analysis ◽  
Evaluation Methodology ◽  
Level Of Evidence ◽  
Assessment Development ◽  
Late Onset Sepsis ◽  
All Cause Mortality

Abstract Objective To systematically review and meta-analyze the role of lactoferrin supplementation to prevent late-onset sepsis (LOS) in preterm infants. Study Design Database search include PubMed, Web of Science, and Cochrane central for randomized clinical trial (RCTs). The Cochrane Grading of Recommendations Assessment, Development, and Evaluation methodology was used for summarizing the results. Results Ten RCTs involving 3,679 infants were included. Lactoferrin supplementation with or without probiotics decreased all LOS (relative risk [RR]: 0.56; 95% confidence interval [CI]: 0.36–0.86; I 2 = 58%; 10 studies; 3,470 subjects; level of evidence [LOE]: low) significantly. Similarly, lactoferrin supplementation without probiotics decreased all LOS (RR: 0.43; 95% CI: 0.29–0.62; I 2 = 0%; 8 studies; 1,209 subjects; LOE: moderate) significantly. Lactoferrin supplementation did not significantly reduce necrotizing enterocolitis (RR: 0.62; 95% CI: 0.29–1.33; I 2 = 43%; 6 studies; 3,079 subjects; LOE: low), all-cause mortality (RR: 0.74; 95% CI: 0.36–1.53; I 2 = 53%; 8 studies; 3,395 subjects; LOE: very low), bronchopulmonary dysplasia (RR: 1; 95% CI: 0.90–1.13; I 2 = 0%; 4 studies; 2,570 subjects; LOE: moderate), and threshold retinopathy of prematurity eligible for surgical treatment (RR: 0.61; 95% CI: 0.25–1.51; I 2 = 74%; 2 studies; 2,481 subjects; LOE: very low). Conclusion Low to moderate quality evidence suggests that lactoferrin supplementation reduces LOS in preterm infants. Further research is needed to improve the certainty in the evidence.

scholarly journals Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

scholarly journals Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hanna Helgeland ◽  
Marte Sodeland ◽  
Nina Zoric ◽  
Jacob Seilø Torgersen ◽  
Fabian Grammes ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Beta Carotene ◽  
Color Variation ◽  
Flesh Color ◽  
Functional Studies ◽  
Genetic Components ◽  
Genome Wide ◽  
A Genome ◽  
Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL- region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

scholarly journals Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

2017 ◽  
Vol 20 (4) ◽  
pp. 267-270 ◽  
Author(s):  
Hamdi Mbarek ◽  
Yuri Milaneschi ◽  
Jouke-Jan Hottenga ◽  
Lannie Ligthart ◽  
Eco J. C. de Geus ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Genome Wide Association Study ◽  
Major Depressive ◽  
Significance Level ◽  
Functional Studies ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10−8) and gene-based (p = 1.48 × 10−7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.

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