Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder

AbstractBackgroundGenetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes.ObjectiveTo identify the association of non-obstructive azoospermia and the putative causative genetic factors.Design, setting, and participantsA single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients’ families.Outcome measurements and statistical analysisWhole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes.Results and limitationsTotally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study.ConclusionsFive novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study.Patient summary133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center.All patients underwent semen analyses at least on three different occasions.

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High-Frequency Exon Deletion of DNA Cross-Link Repair 1C Accounting for Severe Combined Immunodeficiency May Be Missed by Whole-Exome Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2021.677748 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feifan Xiao ◽

Yulan Lu ◽

Bingbing Wu ◽

Bo Liu ◽

Gang Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variant ◽

Severe Combined Immunodeficiency ◽

Cell Receptor ◽

Homozygous Deletion ◽

Combined Immunodeficiency ◽

Cross Link ◽

Single Nucleotide Variants ◽

Whole Exome

Next-generation sequencing (NGS) has been used to detect severe combined immunodeficiency (SCID) in patients, and some patients with DNA cross-link repair 1C (DCLRE1C) variants have been identified. Moreover, some compound variants, such as copy number variants (CNV) and single nucleotide variants (SNV), have been reported. The purpose of this study was to expand the genetic data related to patients with SCID carrying the compound DCLRE1C variant. Whole-exome sequencing (WES) was performed for genetic analysis, and variants were verified by performing Sanger sequencing or quantitative PCR. Moreover, we searched PubMed and summarized the data of the reported variants. Four SCID patients with DCLRE1C variants were identified in this study. WES revealed a homozygous deletion in the DCLRE1C gene from exons 1–5 in patient 1, exons 1–3 deletion and a novel rare variant (c.92T>C, p.L31P) in patient 2, exons 1–3 deletion and a novel rare variant (c.328C>G, p.L110V) in patient 3, and exons 1–4 deletion and a novel frameshift variant (c.449dup, p.His151Alafs*20) in patient 4. Based on literature review, exons 1–3 was recognized as a hotspot region for deletion variation. Moreover, we found that compound variations (CNV + SNV) accounted for approximately 7% variations in all variants. When patients are screened for T-cell receptor excision circles (TRECs), NGS can be used to expand genetic testing. Deletion of the DCLRE1C gene should not be ignored when a variant has been found in patients with SCID.

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Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djx083 ◽

2017 ◽

Vol 109 (12) ◽

Cited By ~ 13

Author(s):

Mykyta Artomov ◽

Alexander J Stratigos ◽

Ivana Kim ◽

Raj Kumar ◽

Martin Lauss ◽

...

Keyword(s):

Association Study ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variant ◽

Whole Exome ◽

Variant Gene

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87. WHOLE-EXOME SEQUENCING IN THE UK BIOBANK REVEALS RISK GENE SLC2A1 AND BIOLOGICAL INSIGHTS FOR MAJOR DEPRESSIVE DISORDER

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.07.173 ◽

2021 ◽

Vol 51 ◽

pp. e87

Author(s):

Ruoyu Tian ◽

Tian Ge ◽

Jimmy Liu ◽

Max Lam ◽

Daniel Levey ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Uk Biobank ◽

Major Depressive ◽

Risk Gene ◽

Whole Exome ◽

The Uk

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Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation

Thrombosis and Haemostasis ◽

10.1160/th16-09-0677 ◽

2017 ◽

Vol 117 (06) ◽

pp. 1083-1092 ◽

Cited By ~ 8

Author(s):

John D. Eicher ◽

Ming-Huei Chen ◽

Achilleas N. Pitsillides ◽

Honghuang Lin ◽

Narayanan Veeraraghavan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Framingham Heart Study ◽

Rare Variants ◽

Platelet Reactivity ◽

Population Based ◽

Association Tests ◽

Whole Exome ◽

Heart Study ◽

Induced Aggregation

SummaryInhibition of platelet reactivity is a common therapeutic strategy in secondary prevention of cardiovascular disease. Genetic and environmental factors influence inter-individual variation in platelet reactivity. Identifying genes that contribute to platelet reactivity can reveal new biological mechanisms and possible therapeutic targets. Here, we examined rare coding variation to identify genes associated with platelet reactivity in a population-based cohort. To do so, we performed whole exome sequencing in the Framingham Heart Study and conducted single variant and gene-based association tests against platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists in up to 1,211 individuals. Single variant tests revealed no significant associations (p<1.44×10–7), though we observed a suggestive association with previously implicated MRVI1 (rs11042902, p = 1.95×10–7). Using gene-based association tests of rare and low-frequency variants, we found significant associations of HYAL2 with increased ADP-induced aggregation (p = 1.07×10–7) and GSTZ1 with increased epinephrine-induced aggregation (p = 1.62×10–6). HYAL2 also showed suggestive associations with epinephrine-induced aggregation (p = 2.64×10–5). The rare variants in the HYAL2 gene-based association included a missense variant (N357S) at a known N-glycosylation site and a nonsense variant (Q406*) that removes a glycophosphatidylinositol (GPI) anchor from the resulting protein. These variants suggest that improper membrane trafficking of HYAL2 influences platelet reactivity. We also observed suggestive associations of AR (p = 7.39×10–6) and MAPRE1 (p = 7.26×10–6) with ADP-induced reactivity. Our study demonstrates that gene-based tests and other grouping strategies of rare variants are powerful approaches to detect associations in population-based analyses of complex traits not detected by single variant tests and possible new genetic influences on platelet reactivity.Supplementary Material to this article is available online at www.thrombosis-online.com.

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