scholarly journals Distribution of rare LOXL1 missense alleles, haplotypes and diplotypes suggests association with reduced risk of glaucoma-related exfoliation syndrome.

2021 ◽  
Author(s):  
Rob P Igo ◽  
Tyler G. Kinzy ◽  
Jessica N. Cooke Bailey ◽  
Chiea Chuen Khor ◽  
Tin Aung ◽  
...  
Keyword(s):  
United States ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Disease Risk ◽  
The United States ◽  
Minor Allele ◽  
Protective Effects ◽  
Exfoliation Syndrome ◽  
Allele Distribution ◽  
Reduced Risk

Purpose: Common LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States. Methods: LOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fisher exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org) and an existing multi-ethnic meta-analysis. Results: Four rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, P<0.001). Conclusions: Using exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.

P–541 Identification of novel variants and candidate genes in women with familial idiopathic premature ovarian failure using whole-exome sequencing

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
R Morale. Sabater ◽  
B Lledo ◽  
J A Ortiz ◽  
F Lozano ◽  
A Bernabeu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Allele Frequency ◽  
Whole Exome Sequencing ◽  
Minor Allele Frequency ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Minor Allele ◽  
Whole Exome

Abstract Study question Is it possible to identify a genetic cause of familial premature ovarian failure (POF) with whole-exome sequencing (WES)? Summary answer Whole-exome sequencing is the most efficient strategy to identify probably pathogenic mutations in different genes in pathologies of polygenic etiology such as premature ovarian failure. What is known already Premature ovarian failure is the loss of ovarian function before the age of 40, and it is a common cause of infertility in women. This pathology has a heterogeneous etiology. Some chromosomal and genetic alterations have been described, and could explain approximately 20% of cases. However, in most patients the origin remains unknown. Recent studies with next-generation sequencing (NGS) have identified new variants in candidate genes related with premature ovarian insufficiency (POI) or premature ovarian failure (POF). These genes are not only involved in processes such as folliculogenesis, but also with DNA damage repair, homologous recombination, and meiosis. Study design, size, duration Fourteen women, from 7 families, affected by idiopathic POF were included in the study from October 2019 to September 2020. Seven POF patients were recruited when they came to our clinic to undergo assisted reproductive treatment. In the anamnesis, it was found that they had relatives with a diagnosis of POF, who were also recruited for the study. The inclusion criteria were amenorrhea before 38 years old and analytical and ultrasound signs of ovarian failure. Participants/materials, setting, methods WES was performed using TrusightOne (Illumina®). Sequenced data were aligned through BWA tool and GATK algorithm was used for SNVs/InDel identification. VCF files were annotated using Variant Interpreter software. Only the variants shared by each family were extracted for analysis and these criteria were followed: (1) Exonic/splicing variants in genes related with POF or involved in biological ovarian functions (2) Variants with minor allele frequency (MAF) ≤0.05 and (3) having potentially moderate/strong functional effects. Main results and the role of chance Seventy-nine variants possibly related with the POF phenotype were identified in the seven families. All these variants had a minor allele frequency (MAF) ≤0.05 in the gnomAD database and 1000 genomes project. Among these candidate variants, two were nonsense, six splice region, one frameshift, two inframe deletion and 68 missense. Thirty-two of the missense variants were predicted to have deleterious effects by minimum two of the four in silico algorithms used (SIFT, PolyPhen–2, MutationTaster and PROVEAN). All variants were heterozygous, and all the families carried three or more candidate variants. Altogether, 43 probably damaging genetic variants were identified in 39 genes expressed in the ovary and related with POF/POI or linked to ovarian physiology. We have described genes that have never been associated to POF pathology, however they may be involved in key biological processes for ovarian function. Moreover, some of these genes were found in two families, for example DDX11, VWF, PIWIL3 and HSD3B1. DDX11 may function at the interface of replication-coupled DNA repair and sister chromatid cohesion. VWF gene is suggested to be associated with follicular atresia in previous studies. PIWIL3 functions in development and maintenance of germline stem cells, and HSD3B1 is implicated in ovarian steroidogenesis. Limitations, reasons for caution Whole-exome sequencing has some limitations: does not cover noncoding regions of the genome, it also cannot detect large rearrangements, copy-number variants (large deletions/duplications), mosaic mutations, mutations in repetitive or high GC rich regions and mutations in genes with corresponding pseudogenes or other highly homologous sequences. Wider implications of the findings: WES has previously shown to be an efficient tool to identify genes as cause of POF, and has demonstrated the polygenic etiology. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POF. Trial registration number Not applicable

MO275RARE VARIANTS OF COMPLEMENT FACTOR H AND THROMBOMODULIN ARE OVER-REPRESENTED IN A COHORT OF SEVERE IGA NEPHROPATHY PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nicolas Maillard ◽  
Veronique Fremeaux Bacchi ◽  
Paula Vieira-Martins ◽  
Perrine Jullien ◽  
Eric Alamartine ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Allele Frequency ◽  
Rare Variant ◽  
Minor Allele Frequency ◽  
Rare Variants ◽  
Regulatory Genes ◽  
Factor H ◽  
Minor Allele ◽  
Risk Haplotype ◽  
Complement Factor

Abstract Background and Aims IgA nephropathy is the most frequent primary glomerulonephritis leading to end stage renal disease (ESRD) in about 30% of cases within 20 years after diagnosis. Complement activation through alternative and lectin pathways has been described to impact the pathogeny of the disease. We hypothesized in this study that rare variants of alternative pathways regulatory genes could be overrepresented and could play a role at initiating the disease and could harm the prognosis of IgA Nephropathy. Method Patients with biopsy proven IgA nephropathy with markers of severity comprising an evolution through ESRD and/or a proteinuria &gt;0.5g/day with available DNA sample were included. All coding sequences of CFH, CFI, MCP, C3, Factor B THBD and CFHR5 genes were analyzed by next generation sequencing. We defined a variant as rare when its minor allele frequency was below 0.1% in the general population. Frequencies were compared to a French volonteers cohort (n=80) and a European large cohort (n=503) Results We screened 128 patients with IgA N, with following characteristics at diagnosis: median age 42.4 yo, proteinuria (median) 1.4g/day, hypertension 66%, median eGFR 48.7 mL/min/1.73m². The median follow-up was 99 months and 58% of patients progressed to ESRD. We identified rare variants with MAF&lt;0.1% in 10.2 % (n=13) including 1 patient with two rare variants. The functional consequences of the 12 out the 14 variants are unknown. Two variants in CFH are located in function domains and are pathogenic. Patients with IgA N have high rates of rare variants in CFH (n=9/128 ; 7 %) versus normal controls (n=9/503 ; 1.8%) (p=0.004); Pathogenic Variants with minor allele frequency &lt;0.1% in CFH were found in 2 IgA N (2 out of 128, 1.5%) versus 1 European controls (1 out of 503) In total, 11 % (14/128), 3.8 % (5/128) and 0.8 % (1/128) of the 128 patients were homozygous for the at-risk haplotype MCP ggaac, CFH tgtgt or both, respectively (versus 6.2 % (5/80), 3.8 % (3/80) and 0% in the controls) 6 patients carried the pathogenic variant in THDM gene p.Ala43Thr (6/128) versus 5 in 508 controls population (p=0.01). No difference in term of hypertension, proteinuria, eGFR, Oxford classification, vascular score at diagnosis was noticed between patients without any rare variant compared to patients with at least one rare variant. The progression through ESRD was not different between groups. Conclusion In this cohort of Caucasian IgA nephropathy patients, rare variants of CFH and THBD were found significantly overrepresented compared to a French and European control cohort. Rare variants of alternative pathway regulatory genes were not associated with particular severity or prognosis.

scholarly journals Genetic Testing by Sports Medicine Physicians in the United States: Attitudes, Experiences, and Knowledge

Sports ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 145
Author(s):  
Eleanor Taranto ◽  
Michael Fishman ◽  
Holly Benjamin ◽  
Lainie Ross
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Sports Medicine ◽  
Injury Risk ◽  
Expert Knowledge ◽  
Disease Risk ◽  
Sickle Cell Trait ◽  
Positive Family History ◽  
The United States ◽  
Medical Society

It remains unknown whether and how sports medicine physicians currently utilize genetic testing in their clinical practice. This study sought to assess knowledge of, experience with, and attitudes towards genetic testing by sports medicine physicians in the United States (US). An email with a survey hyperlink was distributed twice to members of the American Medical Society for Sports Medicine (AMSSM) listserv in September 2016, with approximately a 10% response rate. Questions focused on knowledge of, experience with, and attitudes towards testing for different genes related to sports proficiency, injury risk, and disease risk. Few AMSSM physicians believe that genetic testing to adapt training (12%) or to choose a sport (2%) is ready for clinical adoption. Most respondents self-reported minimal knowledge about, and limited experience with, genetic testing. The main exception was screening for sickle cell trait (SCT) for which most (84%) reported moderate/significant/expert knowledge and over two-thirds had ordered testing. Although most respondents thought it appropriate to counsel and test for health conditions associated with cardiac and connective tissue disorders in the setting of a positive family history, only a minority had been asked to do so. Five or fewer respondents (2%) had been asked to test for performance-associated variants (Angiotensin Converting Enzyme (ACE) II and Alpha-Actinin 3 (ACTN3)), and five or fewer (2%) would recommend changes based on the results. Our study provides a baseline of current US sports medicine physicians’ minimal experiences with, and knowledge of, genetic testing. The findings of our study indicate that sports medicine physicians require further genetics education as it relates to sports and exercise in order to be prepared to competently engage with their patients and to develop sound professional organizational policies.

Abstract 264: Utilizing Risk Scoring for Prescribing Statins to Hospitalized Patients to Primarily Prevent Coronary Artery Disease

2020 ◽  
Vol 13 (Suppl_1) ◽  
Author(s):  
Muhammed Atere ◽  
William Lim ◽  
Vishnuveni Leelaruban ◽  
Bhavya Narala ◽  
Stephanie Herrera ◽  
...  
Keyword(s):  
United States ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
High Risk ◽  
Disease Risk ◽  
The United States ◽  
Intermediate Risk ◽  
Peripheral Artery ◽  
Artery Disease

Background: Cardiovascular disease is the leading cause of mortality in the United States. Approximately 25% of total deaths in the United States are attributed to cardiovascular diseases. Modification of risk factors has been shown to reduce mortality and morbidity in people with coronary artery disease. Medications such as statins are well known for reducing risks and recent data has shown that statins are beneficial in the primary prevention of coronary artery disease. The purpose of this study is to assess whether statins are being prescribed on discharge to patients who are identified as intermediate to high risk using the ACC/AHA Pooled Cohort Equations. Methodology: We reviewed and analyzed the charts of hospitalized patient’s ages 40 to 79 years who were discharged under the service of Internal Medicine at Richmond University Medical Center from September 2018 to August 2019. Exclusion criteria included: patients that expired before discharge or were admitted to the intensive or coronary care units, pregnancy, previous diagnosis of coronary/peripheral artery disease or stroke, already on statins or lipid-lowering medications, allergic to statins, discharged on statins for coronary/peripheral artery disease or stroke, and patients with liver disease or elevated liver enzymes. We used the ACC/AHA Pooled Cohort Equations risk to calculate the 10-year coronary artery disease risk for each patient. Results: The 10-year risk is grouped as low risk (<5%), borderline risk (5% to 7.4%), intermediate risk (7.5% to 19.9%) and high risk (≥20%). Among 898 patients, 10% had intermediate and high risk that were not discharged with statins. Among the 10%, about 6.6% were intermediate risk and 3.4% were high risk. Conclusions: A significant number of intermediate and high-risk patients were discharged without statins, although a CT coronary calcium may be helpful in further classifying the risk in some of them. We believe that a lipid profile should be checked in all hospitalized patients 40 years and older in order to calculate their atherosclerosis cardiovascular disease risk score and to possibly initiate statins after discussing the benefits and side effects, particularly in the intermediate risk group. The continuation of statins would be followed up by their primary care physicians. We plan to liaise with the information technology department in our facility to provide a link to the risk calculator in the electronic medical record so that the risk can be calculated and statins initiated as necessary. We will conduct a follow up review to assess for effectiveness.

Abstract 468: Previously Unrecognized Intronic Variants in the Dystrophin Gene Identified as Possible Contributors to Dilated Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Alex Gyftopoulos ◽  
Tamara Ashvetiya ◽  
Yi-Ju Chen ◽  
Libin Wang ◽  
Charles H Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Mixed Model ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Minor Allele ◽  
Intronic Variants

Nonischemic dilated cardiomyopathy (DCM) often has a genetic etiology, however, its prevalence and etiologies are not completely understood. The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals with enrollees 40-69 years of age. Our group created a custom phenotype of heart failure using ICD-10 codes for several subtypes of heart failure diagnoses including DCM. We then compared the individuals included in the custom heart failure phenotype to control individuals in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. We identified 8 unlinked intronic variants in the dystrophin gene ( DMD ) that, when separated by self-identified race, occurred with a combined minor allele frequency of 0.15 in individuals with heart failure who identified as being of African descent. The combined minor allele frequency of these variants was 0.05 in individuals who self-identified as being of European descent. One variant of DMD in particular (rs139029250), was identified with a minor allele frequency of 0.05 in African British with DCM. The unadjusted odds ratio of a diagnosis of heart failure in individuals with rs129029250 was 4.65. When separated by gender, the unadjusted odds ratios are 2.02 for females and 6.44 for males. DMD is most notably known for its role in Duchenne and Becker muscular dystrophy, both of which are known to cause dilated cardiomyopathy in affected individuals. However, none of the individuals (36 female and 43 male) identified in our analysis with rs129029250 have been diagnosed with Duchenne muscular dystrophy, Becker muscular dystrophy, or a primary disorder of muscle (ICD code G70). Additionally, these individuals have an intronic variant of DMD , while Duchene and Becker muscular dystrophy are both due to exonic mutations. These findings suggest a possible common variant in the DMD gene that may contribute to DCM in individuals of African descent.

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