scholarly journals Quantifying genetic regulatory variation in human populations improves transcriptome analysis in rare disease patients

2019 ◽  
Author(s):  
Pejman Mohammadi ◽  
Stephane E. Castel ◽  
Beryl B. Cummings ◽  
Jonah Einson ◽  
Christina Sousa ◽  
...  
Keyword(s):  
Rare Disease ◽  
Gene Dosage ◽  
Basic Research ◽  
Selective Constraint ◽  
Allelic Expression ◽  
Human Populations ◽  
Regulatory Variation ◽  
Outlier Test ◽  
Pathogenic Variants ◽  
Regulatory Variant

AbstractTranscriptome data holds substantial promise for better interpretation of rare genetic variants in basic research and clinical settings. Here, we introduce ANalysis of Expression VAriation (ANEVA) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application to GTEx data showed that this variance estimate is robust across datasets and is correlated with selective constraint in a gene. We next used ANEVA variance estimates in a Dosage Outlier Test (ANEVA-DOT) to identify genes in an individual that are affected by a rare regulatory variant with an unusually strong effect. Applying ANEVA-DOT to AE data form 70 Mendelian muscular disease patients showed high accuracy in detecting genes with pathogenic variants in previously resolved cases, and lead to one confirmed and several potential new diagnoses in cases previously unresolved. Using our reference estimates from GTEx data, ANEVA-DOT can be readily incorporated in rare disease diagnostic pipelines to better utilize RNA-seq data.One Sentence SummaryNew statistical framework for modelling allelic expression characterizes genetic regulatory variation in populations and informs diagnosis in rare disease patients

scholarly journals Genetic regulatory variation in populations informs transcriptome analysis in rare disease

Science ◽  
2019 ◽  
Vol 366 (6463) ◽  
pp. 351-356 ◽  
Author(s):  
Pejman Mohammadi ◽  
Stephane E. Castel ◽  
Beryl B. Cummings ◽  
Jonah Einson ◽  
Christina Sousa ◽  
...  
Keyword(s):  
Rare Disease ◽  
Gene Dosage ◽  
Selective Constraint ◽  
Sequencing Data ◽  
Outlier Test ◽  
Pathogenic Variants ◽  
Muscular Disease ◽  
Rare Genetic Variants ◽  
Variance Estimate ◽  
Variance Estimates

Transcriptome data can facilitate the interpretation of the effects of rare genetic variants. Here, we introduce ANEVA (analysis of expression variation) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application of ANEVA to the Genotype-Tissues Expression (GTEx) data showed that this variance estimate is robust and correlated with selective constraint in a gene. Using these variance estimates in a dosage outlier test (ANEVA-DOT) applied to AE data from 70 Mendelian muscular disease patients showed accuracy in detecting genes with pathogenic variants in previously resolved cases and led to one confirmed and several potential new diagnoses. Using our reference estimates from GTEx data, ANEVA-DOT can be incorporated in rare disease diagnostic pipelines to use RNA-sequencing data more effectively.

scholarly journals Evolutionary history of regulatory variation in human populations

2010 ◽  
Vol 19 (R2) ◽  
pp. R197-R203 ◽  
Author(s):  
T. Lappalainen ◽  
E. T. Dermitzakis
Keyword(s):  
Evolutionary History ◽  
Human Populations ◽  
Regulatory Variation ◽  
History Of

scholarly journals Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Elias L. Salfati ◽  
Emily G. Spencer ◽  
Sarah E. Topol ◽  
Evan D. Muse ◽  
Manuel Rueda ◽  
...  
Keyword(s):  
Sudden Death ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Diagnostic ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

GeneBreaker - Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

2020 ◽  
Author(s):  
Phillip A. Richmond ◽  
Tamar V. Av-Shalom ◽  
Oriol Fornes ◽  
Bhavi Modi ◽  
Alison M. Elliott ◽  
...  
Keyword(s):  
Rare Disease ◽  
Genetic Diseases ◽  
Genomic Medicine ◽  
Real Life ◽  
Variant Calling ◽  
Pathogenic Variants ◽  
Rare Genetic Diseases ◽  
Diagnosis Rate ◽  
Effective Use ◽  
Potential Pathogenicity

AbstractMendelian rare genetic diseases affect 5-10% of the population, and with over 5,300 genes responsible for ~7,000 different diseases, they are challenging to diagnose. The use of whole genome sequencing (WGS) has bolstered the diagnosis rate significantly. Effective use of WGS relies upon the ability to identify the disrupted gene responsible for disease phenotypes. This process involves genomic variant calling and prioritization, and is the beneficiary of improvements to sequencing technology, variant calling approaches, and increased capacity to prioritize genomic variants with potential pathogenicity. As analysis pipelines continue to improve, careful testing of their efficacy is paramount. However, real-life cases typically emerge anecdotally, and utilization of clinically sensitive and identifiable data for testing pipeline improvements is regulated and limiting. We identified the need for a gene-based variant simulation framework which can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene-disrupting variants. To fill this need, we present GeneBreaker, a tool which creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for training diagnostic practitioners in the expanding field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.

scholarly journals 2484

2017 ◽  
Vol 1 (S1) ◽  
pp. 80-81
Author(s):  
Tilicia Mayo-Gamble ◽  
Velma McBride Murry ◽  
Michael R. DeBaun
Keyword(s):  
Rare Disease ◽  
Sickle Cell ◽  
Process Model ◽  
Basic Research ◽  
Standard Of Care ◽  
Healthcare Services ◽  
Valuable Insight ◽  
Patient Centered ◽  
Research Activities ◽  
Rural And Urban

OBJECTIVES/SPECIFIC AIMS: Despite the high prevalence of individuals diagnosed with sickle cell disease (SCD) in Tennessee, comprehensive care and education for patients with SCD is not as widely available as healthcare services for individuals managing other chronic illnesses. We aimed to engage SCD stakeholders in patient-centered outcomes research (PCOR) as a mechanism for advancing care and translational research for this rare disease population. METHODS/STUDY POPULATION: Through a partnership with the Sickle Cell Foundation of Tennessee, we implemented Community Health Ambassadors to systematically engage patient partners with SCD and their caregivers, aged 18–50 from rural and urban communities throughout Tennessee, in PCOR to establish a sustainable infrastructure, focused on connecting the SCD community through a service providing community-based organization to offer (1) information on how to connect with other families; and be informed about SCD community activities, or educational offerings; (2) training in basic research principals; and (3) opportunities to contribute to PCOR, including feedback on effective and practical ways for providing input on research efforts through patient centered input, comparing urban and rural area preferences. Community ambassadors utilized health fairs, clinic days at various hospitals and community centers, and social media to spread awareness of the project, in addition to boosting the recruitment process. RESULTS/ANTICIPATED RESULTS: A statewide SCD network was developed to offer social support and increase access to education, medical care, and engagement in research activities. Findings include: recruitment of 150 patients and 35 executive committee members (local physicians, community leaders, adults with SCD and parents of children with SCD). DISCUSSION/SIGNIFICANCE OF IMPACT: Most rural and urban families affected by SCD have no systematic way to engage in, or lend their expertise to, PCOR. A statewide network of patient partners, community stakeholders, researchers, and medical professionals will ultimately increase the standard of care for patients, and provide valuable insight for SCD research. The opportunity to create the underpinnings for coordinated patient-centered education for patients with SCD and their caregivers holds promise for developing a scalable PCOR process model for replication and implementation in other states and emulate this model with other rare disease populations.

scholarly journals A flexible computational pipeline for research analyses of unsolved clinical exome cases

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Timo Lassmann ◽  
Richard W. Francis ◽  
Alexia Weeks ◽  
Dave Tang ◽  
Sarra E. Jamieson ◽  
...  
Keyword(s):  
Open Access ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Gene Variant ◽  
Computational Pipeline ◽  
Patient Report ◽  
Web Based ◽  
Pathogenic Variants ◽  
Flexible Framework ◽  
Disease Variant

AbstractExome sequencing has enabled molecular diagnoses for rare disease patients but often with initial diagnostic rates of ~25−30%. Here we develop a robust computational pipeline to rank variants for reassessment of unsolved rare disease patients. A comprehensive web-based patient report is generated in which all deleterious variants can be filtered by gene, variant characteristics, OMIM disease and Phenolyzer scores, and all are annotated with an ACMG classification and links to ClinVar. The pipeline ranked 21/34 previously diagnosed variants as top, with 26 in total ranked ≤7th, 3 ranked ≥13th; 5 failed the pipeline filters. Pathogenic/likely pathogenic variants by ACMG criteria were identified for 22/145 unsolved cases, and a previously undefined candidate disease variant for 27/145. This open access pipeline supports the partnership between clinical and research laboratories to improve the diagnosis of unsolved exomes. It provides a flexible framework for iterative developments to further improve diagnosis.

Viral Disease in Hematology

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 409-423 ◽  
Author(s):  
Genoveffa Franchini ◽  
Richard F. Ambinder ◽  
Michèle Barry
Keyword(s):  
Leukemia Virus ◽  
Antiviral Treatment ◽  
Basic Research ◽  
Epidemiological Data ◽  
Viral Disease ◽  
Human Populations ◽  
Genetic Characteristics ◽  
Barr Virus ◽  
Ebv Infection ◽  
Human T Cell

As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies.In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies.In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.

scholarly journals Sex-biased reduction in reproductive success drives selective constraint on human genes

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Matthew D. C. Neville ◽  
Kaitlin E. Samocha ◽  
Kieron Barclay ◽  
Martin Kolk ◽  
...  
Keyword(s):  
Sexual Selection ◽  
Reproductive Success ◽  
Genetic Variants ◽  
Purifying Selection ◽  
Female Mate Choice ◽  
Selective Constraint ◽  
Human Populations ◽  
Protein Coding ◽  
Genome Wide ◽  
Human Genes

SummaryGenome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show that genetic variants that damage these genes reduce reproductive success substantially in males but much less so in females. We present evidence that this reduction is mediated primarily by cognitive and behavioural traits, which renders male carriers of such variants less likely to find mating partners. These findings represent strong genetic evidence that sexual selection mediated through female mate choice is shaping the gene pool of contemporary human populations. Furthermore, these results suggest that sexual selection accounts for 21% of purifying selection against heterozygous variants that ablate protein-coding genes.

scholarly journals Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing

2020 ◽  
Vol 21 (23) ◽  
pp. 9238
Author(s):  
Chi-Hsiao Yeh ◽  
Yi-Ju Chou ◽  
Cheng-Heng Kao ◽  
Ting-Fen Tsai
Keyword(s):  
Energy Metabolism ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Dynamic Control ◽  
Basic Research ◽  
Human Populations ◽  
Age Related ◽  
Novel Target ◽  
High Level ◽  
New Evidence

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria–lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing

scholarly journals SUN-600 Presence of LMNA p.R582H Pathogenic Variant in Homozygous State Demonstrates Gene Dosage Effect on the Severity of Fat Loss in Lipodystrophy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Utku Erdem Soyaltin ◽  
Ilgin Yildirim Simsir ◽  
Baris Akinci ◽  
Canan Altay ◽  
Suleyman Cem Adiyaman ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Pathogenic Variant ◽  
Dosage Effect ◽  
Lamin A ◽  
Lmna Gene ◽  
Homozygous State ◽  
Gene Dosage Effect ◽  
Fat Loss ◽  
Genital Region ◽  
Pathogenic Variants

Abstract Background Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants, and a few patients have been associated with generalized fat loss. Clinical Case Here, we report a patient with lamin A specific pathogenic variant at exon 11 LMNA p.R582H present in homozygous state. Fat distribution was compared radiographically to a heterozygote LMNA p.R582H patient from another pedigree, female healthy control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, n = 9) and typical FPLD2 (n = 8). The whole body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, homozygous p.R582H LMNA variant was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, heterozygous LMNA p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482. Conclusions Our observations and radiological comparisons demonstrate a gene dosage effect of LMNA variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the LMNA gene, our observation suggests that genetic factors modulate the extent of fat loss in LMNA associated lipodystrophy.

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