36. Classifying benign multigenic CNVs: Exploring available population databases

AbstractMutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early onset Parkinson’s Disease (PD). Hundreds of naturally occurring Parkin variants have been reported, both in PD patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remains unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence – including measures of mitophagy and protein stability, and predictive structural modeling – and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

Download Full-text

Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

Cardiologia Hungarica ◽

10.26430/chungarica.2021.51.2.118 ◽

2021 ◽

Vol 51 (2) ◽

pp. 118-124

Author(s):

Arnold Péter Ráduly ◽

Attila Tóth ◽

Zoltán Papp ◽

Attila Borbély

Keyword(s):

Genetic Testing ◽

Expert Panel ◽

Clinical Care ◽

Cardiovascular Disorder ◽

Chain Gene ◽

Web Based ◽

Inherited Cardiomyopathy ◽

Omecamtiv Mecarbil ◽

Next Generation Sequencing Ngs ◽

Population Databases

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

Download Full-text

From Population Databases to Research and Informed Health Decisions and Policy

Frontiers in Public Health ◽

10.3389/fpubh.2017.00230 ◽

2017 ◽

Vol 5 ◽

Cited By ~ 3

Author(s):

Yossy Machluf ◽

Orna Tal ◽

Amir Navon ◽

Yoram Chaiter

Keyword(s):

Health Decisions ◽

Population Databases

Download Full-text

0408 Workers’ exposure to brominated flame retardants: a glance at american and canadian population databases

10.1136/oemed-2017-104636.336 ◽

2017 ◽

Author(s):

Sabrina Gravel ◽

Jérôme Lavoué ◽

France Labrèche

Keyword(s):

Flame Retardants ◽

Brominated Flame Retardants ◽

Canadian Population ◽

Population Databases

Download Full-text

P1785Whole exome sequencing unravels new genes associated with mitral valve prolapse

European Heart Journal ◽

10.1093/eurheartj/ehz748.0537 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Van Wijngaarden ◽

Y L Hiemstra ◽

T T Koopmann ◽

C A L Ruivenkamp ◽

E Aten ◽

...

Keyword(s):

Mental Retardation ◽

Mitral Valve ◽

Exome Sequencing ◽

Mitral Valve Prolapse ◽

Pathogenic Variant ◽

Pathogenic Variants ◽

Cardiac Phenotype ◽

Variant Of Unknown Significance ◽

Unknown Significance ◽

Population Databases

Abstract Background Several studies have suggested a familial clustering of mitral valve prolapse (MVP), especially for Barlow disease (BD), which is regarded as the effect of genetic or developmental errors. However, the genetic etiology of MVP, in particular BD, is largely unknown. So far only three genes have been identified: FLNA, DCHS1 and PLD1. Purpose The aim of this study was to identify genes associated with MVP using whole exome sequencing (WES). Methods Patients with MVP, who were classified as BD and/or had a positive family history for MVP, were referred for genetic counseling and WES. In total, 106 unrelated probands were included to identify potentially pathogenic variants in a set of 551 genes associated with cardiovascular development and/or diseases. The population databases Genome Aggregation and WES data from 110 parents of children with mental retardation were used as controls. Variants were analyzed using prediction programs, frequency in the population database and literature search. Variants were divided into the following categories: likely benign, variant of unknown significance or likely pathogenic. Results Thirteen percent (14/106) of the probands had a likely pathogenic variant in seven different genes: DCHS1 (1x), DSP (1x), HCN4 (2x), MYH6 (1x), TMEM67 (1x), TRPS1 (1x) and TTN (7x); the DSP, MYH6 and HCN4 variants cosegregated in affected relatives. None of the 110 parents of children with mental retardation had a likely pathogenic variant in these seven genes. In addition, 31% (33/106) of the probands harbored a variant of unknown significance in 23 different genes, including the genes DSP, FLNA, MYH6 and TTN (Fig). Remarkable, one variant of unknown significance in the FBN2 gene was shared among three unrelated probands and did not occur in population databases. Conclusion WES analysis conducted in probands with MVP using a large panel of genes associated with cardiac development and/or disease confirmed previously known causative genes (DCHS1) and expanded the cardiac phenotype of genes originally associated with cardiomyopathy (DSP, HCN4, MYH6 and TTN). This study is the first study that described the association between MVP and the genes DSP, MYH6 and TTN although the pathogenesis is still unknown. This high yield of likely pathogenic variants emphasizes the importance of genetic screening in MVP patients.

Download Full-text

A Data Preparation Methodology in Data Mining Applied to Mortality Population Databases

Journal of Medical Systems ◽

10.1007/s10916-015-0312-5 ◽

2015 ◽

Vol 39 (11) ◽

Cited By ~ 3

Author(s):

Joaquín Pérez ◽

Emmanuel Iturbide ◽

Víctor Olivares ◽

Miguel Hidalgo ◽

Alicia Martínez ◽

...

Keyword(s):

Data Mining ◽

Data Preparation ◽

Population Databases

Download Full-text

Development of Residential Building Stock and Population Databases and Modeling the Residential Occupancy Rate for Iran

Natural Hazards Review ◽

10.1061/(asce)nh.1527-6996.0000109 ◽

2014 ◽

Vol 15 (1) ◽

pp. 88-94 ◽

Cited By ~ 4

Author(s):

Babak Mansouri ◽

Kambod Amini-Hosseini

Keyword(s):

Residential Building ◽

Occupancy Rate ◽

Building Stock ◽

Residential Building Stock ◽

Population Databases

Download Full-text

Genetic variation at 27 y-strs in four regions of bahrain

10.1101/787341 ◽

2019 ◽

Cited By ~ 1

Author(s):

Noora R. Al-Snan ◽

Safia A. Messaoudi ◽

Yahya M. Khubrani ◽

Jon H. Wetton ◽

Mark A. Jobling ◽

...

Keyword(s):

Tandem Repeats ◽

Indigenous Population ◽

Arabian Gulf ◽

Northern Region ◽

Rapid Expansion ◽

Population Substructure ◽

Social Variation ◽

Geographical Regions ◽

Population Databases ◽

Short Tandem

AbstractBahrain location in the Arabian Gulf contributed to the diversity of its indigenous population descended from Christian Arabs, Persians (Zoroastrians), Jews, and Aramaic-speaking agriculturalists. The aim of this study was to examine population substructure within Bahrain using the 27 Y-STRs (short tandem repeats) in the Yfiler Plus kit and to characterize the haplotypes of 562 unrelated Bahraini nationals, sub-divided into the four geographical regions - North, Capital, South and Muharraq. Yfiler Plus provided a significant improvement over the earlier 17-locus Yfiler kit in discrimination capacity, increasing it from 77% to 87.5%, but this value differed widely between regions from 98.4% in Muharraq to 75.2% in the Northern region, an unusually low value possibly as a consequence of the very rapid expansion in population size in the last 80 years. Clusters of closely related male lineages were seen, with only 79.4% of donors displaying unique haplotypes and 59% of instances of shared haplotypes occurring within, rather than between, regions. Haplogroup prediction indicated diverse origins of the population with a predominance of haplogroups J2 and J1, both typical of the Arabian Peninsula, but also haplogroups such as B2 and E1b1a originating in Africa and H, L and R2 indicative of migration from the east. Haplogroup frequencies differed significantly between regions with J2 significantly more common in the Northern region compared with the Southern possibly as a result of differential settlement with Baharna (descended from populations in which J2 predominates) and Arabs (both indigenous and migrant Huwala who are expected to have a higher frequency of J1). Our study illustrated the importance of encompassing geographical and social variation when constructing population databases and the need for highly discriminating multiplexes where rapid expansions have occurred within tightly bounded populations.

Download Full-text

Overestimation of tumor mutational burden (TMB) using algorithms compared to germline subtraction.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2621 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2621-2621

Author(s):

Kaushal Parikh ◽

Robert Huether ◽

Kevin White ◽

Derick Hoskinson ◽

Haidong Dong ◽

...

Keyword(s):

Germline Variation ◽

Tumor Mutational Burden ◽

Level 3 ◽

Somatic Alterations ◽

Level 1 ◽

The Difference ◽

Clinical Trial Results ◽

Population Databases ◽

Allelic Fraction ◽

Level 2

2621 Background: TMB is an emerging predictor of survival with immunotherapy. TMB is determined by taking the difference between somatic and germline datasets when tumor-normal pairs are available. In the case of commonly utilized tumor-only sequencing, additional steps are needed to estimate the somatic alterations. Computational tools have been developed that determine germline contribution based on sample copy state, purity estimates and occurrence of the variant in population databases. Given the potential bias of population datasets, we hypothesized that tumor-only filtering approaches may overestimate the actual TMB. Methods: We assessed the TMB from 50 tumors in 10 diseases including all missense, indels, and frameshift variants with an allelic fraction (AF) ≥5% and Coverage ≥100X within the tumor. Tumor-only TMB was evaluated against the gold standard of matched germline subtracted TMB at three levels. Level 1 removed all the tumor-only variants with AF in the non-TCGA ExAC database ≥1%. Level 2 removed all variants observed in population databases simulating a naive approach of removing germline variation. Level 3 used an internal tumor-only pipeline for calculating TMB. Results: There were significantly higher estimates of TMB with Level 1, Level 2 and Level 3 tumor-only filtering approaches than that determined by germline subtraction, resulting in significant bias. Whereas there was no correlation between TMB estimates and tumor-germline TMB for Level 1 filtering, there were improvements in correlations for Level 2 and Level 3. Conclusions: The tumor-only approaches that filter variants in population databases overestimate TMB compared to that determined by germline subtraction. Despite improved correlations with more stringent filtering approaches, these falsely elevated estimates may result in the inappropriate categorization of tumor specimens and negatively impact clinical trial results and patient outcomes. [Table: see text]

Download Full-text