scholarly journals Two Rare Variants in PLAU and BACE1 Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1806
Author(s):  
Katarzyna Gaweda-Walerych ◽  
Emilia J. Sitek ◽  
Małgorzata Borczyk ◽  
Mariusz Berdyński ◽  
Ewa Narożańska ◽  
...  
Keyword(s):  
Early Onset ◽  
Rare Variants ◽  
Missense Variant ◽  
Underlying Mechanism ◽  
Semantic Dementia ◽  
Mrna Levels ◽  
Protein Levels ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in β-site APP-cleaving enzyme 1 (BACE1)—along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Systematic analysis of PINK1 variants of unknown significance shows intact mitophagy function for most variants

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kai Yu Ma ◽  
Michiel R. Fokkens ◽  
Teus van Laar ◽  
Dineke S. Verbeek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Missense Variant ◽  
Population Based ◽  
Loss Of Function ◽  
Systematic Analysis ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Disease Case ◽  
Unknown Significance

AbstractPathogenic variants in PINK1 cause early-onset Parkinson’s disease. Although many PINK1 variants have been reported, the clinical significance is uncertain for the majority of them. To gain insights into the consequences of PINK1 missense variants in a systematic manner, we selected 50 PINK1 missense variants from patient- and population-wide databases and systematically classified them using Sherloc, a comprehensive framework for variant interpretation based on ACMG-AMP guidelines. We then performed functional experiments, including mitophagy and Parkin recruitment assays, to assess the downstream consequences of PINK1 variants. Analysis of PINK1 missense variants based on Sherloc showed that the patient databases over-annotate variants as likely pathogenic. Furthermore, our study shows that pathogenic PINK1 variants are most often linked to a loss-of-function for mitophagy and Parkin recruitment, while this is not observed for variants of unknown significance. In addition to the Sherloc framework, the added layer of evidence of our functional tests suggests a reclassification of 9/50 missense variants. In conclusion, we suggest the assessment of multiple layers of evidence, including functional data on top of available clinical and population-based data, to support the clinical classification of a variant and show that the presence of a missense variant in PINK1 in a Parkinson’s disease case does not automatically imply pathogenicity.

scholarly journals Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients

2021 ◽  
Author(s):  
Stefania Mantovani ◽  
Sergio Daga ◽  
Chiara Fallerini ◽  
Margherita Baldassarri ◽  
Elisa Benetti ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Rare Variants ◽  
Functional Characterization ◽  
Prior History ◽  
Type I ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Peripheral Blood Mononuclear ◽  
Antiviral Responses ◽  
History Of

AbstractToll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

scholarly journals Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1299
Author(s):  
Alice Grossi ◽  
Maurizio Miano ◽  
Marina Lanciotti ◽  
Francesca Fioredda ◽  
Daniela Guardo ◽  
...  
Keyword(s):  
Rare Variants ◽  
Causative Gene ◽  
Inborn Errors ◽  
Variants Of Unknown Significance ◽  
Inborn Errors Of Immunity ◽  
Complex Patients ◽  
Unknown Significance ◽  
Gene Panels ◽  
Clinical Pictures ◽  
Next Generation Sequencing Ngs

Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients’ phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.

PTEN Promoter Variants Are Not Associated With Common Cancers: Implications for Multigene Panel Testing

2017 ◽  
pp. 1-7 ◽  
Author(s):  
Mary Helen Black ◽  
Shuwei Li ◽  
Tina Pesaran ◽  
Holly LaDuca ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Personal History ◽  
Variants Of Unknown Significance ◽  
Panel Testing ◽  
Multiple Primary ◽  
Unknown Significance ◽  
Uterine Endometrial Cancer ◽  
History Of ◽  
Race Ethnicity ◽  
Multigene Panel Testing ◽  
Multigene Panel

Purpose PTEN mutations are associated with breast, colon, endometrial, kidney, and thyroid cancers. Most PTEN promoter alterations, however, are characterized as variants of unknown significance, and their contribution to cancer risk is unclear. Materials and Methods Personal and family histories of 88,333 patients undergoing PTEN analysis as part of multigene panel testing (MGPT) were retrospectively reviewed. Cases (n = 59,784) were individuals with personal history of PTEN-related cancer. Controls (n = 28,549) had no personal history of cancer. Individuals were categorized as positive for one or more mutations (PATHO), without mutations but carrying one or more promoter variant (PROM), or negative for alterations (WT). Multivariable logistic regression was used to assess PTEN associations with phenotypes, adjusted for race/ethnicity, age, sex, and MGPT. Results Overall, 79 (0.09%) patients were PATHO and 791 (0.9%) were PROM carriers. Compared with WT, PATHOs were 2.30 (95% CI, 1.19 to 4.72) times as likely to have breast, 7.23 (95% CI, 2.74 to 19.14) times as likely to have bilateral/multiple primary breast, and 7.56 (95% CI, 1.97 to 23.98) times as likely to have uterine/endometrial cancer. PROMs were not significantly more likely than WT to have cancer (all 0.84 < odds ratio < 1.15; P > .05). Conclusion PTEN promoter variants were not associated with cancer. These results do not support the inclusion of PTEN promoter sequencing in MGPT.

scholarly journals Variants in HNRNPDL and SETX Not Necessarily Indicate Familial Amyotrophic Lateral Sclerosis or Limb Girdle Muscular Dystrophy 1G in Acute Muscular Respiratory Failure

2020 ◽  
Vol 11 (02) ◽  
pp. 353-354
Author(s):  
Josef Finsterer ◽  
Claudia Stöllberger ◽  
Hans Keller ◽  
Franco Laccone
Keyword(s):  
Respiratory Failure ◽  
Variants Of Unknown Significance ◽  
Non Invasive ◽  
Non Invasive Ventilation ◽  
Unknown Significance ◽  
History Of ◽  
History Of Epilepsy ◽  
Diagnostic Work ◽  
Conclusive Diagnosis ◽  
Work Up

AbstractGenetic work-up is useful for the identification of a primary myopathy. However, even sophisticated genetic methods may fail to detect the underlying cause of myopathy as in the following case. The patient is a 52-year-old female with a history of epilepsy, arterial hypertension, atrial flutter requiring cardioversion, ablation, and anticoagulation, coronary heart disease, hyperlipidemia, and hyper-CKemia. At age 52 years, she was referred for heart failure due to ischemic cardiomyopathy requiring appropriate medication and implantation of an ICD. During hospitalization she developed acute muscular respiratory failure requiring mechanical ventilation. Genetic panels for myopathy, neuropathy, and cardiomyopathy revealed variants of unknown significance in the HNRNPDL and SETX genes respectively. Clinical presentation and muscle biopsy, however, suggested metabolic myopathy. Acute muscular respiratory failure may require traditional diagnostic work-up for primary myopathy and long-term invasive and non-invasive ventilation. Panel investigations not necessarily lead to a conclusive diagnosis. The multisystem nature of the condition rather suggests a metabolic defect than LGMD-1G or fALS as genetic findings suggested.

scholarly journals Yiqi Huoxue Recipe Improves Liver Regeneration in Rats after Partial Hepatectomy via JNK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Wen-cong Li ◽  
Su-xian Zhao ◽  
Wei-guang Ren ◽  
Hui-juan Du ◽  
Yu-guo Zhang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Protective Effects ◽  
Jnk Pathway ◽  
Expression Levels ◽  
Protein Levels ◽  
Mrna And Protein Expression

The liver is the only visceral organ that exhibits a remarkable capability of regenerating in response to partial hepatectomy (PH) or chemical injury. Improving liver regeneration (LR) ability is the basis for the favourable treatment outcome of patients after PH, which can serve as a potential indicator for postoperative survival. The present study aimed to investigate the protective effects of Yiqi Huoxue recipe (YQHX) on LR after PH in rats and further elucidate its underlying mechanism. A two-thirds PH rat model was used in this study. Wistar rats were randomly divided into four groups: sham-operated, PH, YQHX + PH, and Fuzheng Huayu decoction (FZHY) + PH groups. All rats were sacrificed under anesthesia at 24 and 72 h after surgery. The rates of LR were calculated, and the expression levels of cyclin D1 and c-jun were determined by immunohistochemical staining. The protein levels of p-JNK1/2, JNK1/2, p-c-jun, c-jun, Bax, and Bcl-2 were detected by Western blotting, while the mRNA levels of JNK1, JNK2, c-jun, Bax, and Bcl-2 were examined by real-time polymerase chain reaction (RT-PCR). At the corresponding time points, YQHX and FZHY administration dramatically induced the protein levels of p-JNK1/2 compared to the PH group p<0.05, while FZHY + PH group showed prominently increase in p-JNK1/2 protein levels compared to the YQHX + PH group p<0.05. A similar trend was observed for the expression levels of p-c-jun. Compared to the PH group, YQHX and FZHY markedly reduced the mRNA and protein expression levels of Bax at 24 h after PH, while those in the FZHY + PH group decreased more obviously p<0.05. Besides, in comparison with the PH group, YQHX and FZHY administration predominantly upregulated the mRNA and protein expression levels of Bcl-2 at 24 and 72 h after PH p<0.05. In conclusion, YQHX improves LR in rats after PH by inhibiting hepatocyte apoptosis via the JNK signaling pathway.

The incidence of BRCA1 and BRCA2 variants of unknown significance varies in different ethnic populations

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10002-10002 ◽  
Author(s):  
D. M. Opatt ◽  
M. Morrow ◽  
M. Daly
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Genetic Testing ◽  
African American Women ◽  
White Women ◽  
Personal History ◽  
Brca1 And Brca2 ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

Use of PTEN protein dosage to predict for underlying germ-line PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1508-1508
Author(s):  
Joanne Y. Y. Ngeow ◽  
Xin He ◽  
Jessica Mester ◽  
Deepa Radhakrishnan ◽  
Junying Lei ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Germ Line ◽  
Cowden Syndrome ◽  
Pten Protein ◽  
Protein Levels ◽  
Variants Of Unknown Significance ◽  
Pten Mutation ◽  
Increased Risk ◽  
Unknown Significance ◽  
Cost Efficient

1508 Background: Thyroid cancer is a major component of Cowden Syndrome (CS), a heritable syndrome characterized also by breast, uterine and kidney cancers. CS patients with an underlying germline PTEN mutation have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, <1% of sporadic epithelial thyroid cancer harbor a germline PTEN mutation. Thus, cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Here, we analyzed the relationship of patient PTEN protein levels in predicting the presence of germline PTEN mutations. Methods: We conducted a 5-year, multi-center prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared PTEN protein expression levels between patients with pathogenic PTEN mutations (PTENmut+), and those with variants of unknown significance (VUS) or wildtype PTEN. PTEN immunohistochemistry (IHC) was performed on available thyroid samples. Results: Of 2792 CS/CS-like patients, 722 had thyroid cancer. PTEN germline pathogenic mutations were present in 36/722 (5%) patients. PTENmut+ cases presented at an earlier age (35 vs 42 years; p=0.02). PTEN frameshift and truncation mutations accounted for 55% of mutations. 95% (19/20) of PTENmut+ patients had blood-PTEN protein levels in the lowest quartile as compared to 27% (90/330) of PTEN wildtype/PTEN VUS patients (p<0.001). Low blood-PTEN levels predicted for PTENmut+ cases with a 99.6 % NPV (95%CI 97.7- 99.9) and a positive test likelihood ratio of 3.5 (95%CI 2.8-4.3). Affected thyroid tissues (n=22) from PTENmut+ cases showed loss of PTEN protein by IHC, correlating with patient blood PTEN levels (r2=0.30, p=0.016). Conclusions: Our study shows that PTEN protein dosage could serve as a molecular correlate predicting for germline PTEN mutation in CS and CS-like presentations of thyroid cancer. The clinical utility of PTEN IHC in identifying thyroid cancer patients for germline PTEN testing should be further explored.

scholarly journals Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Hang Yang ◽  
Yanyun Ma ◽  
Mingyao Luo ◽  
Guoyan Zhu ◽  
Yinhui Zhang ◽  
...  
Keyword(s):  
Rare Variants ◽  
Cardiovascular Death ◽  
Connective Tissue Disorder ◽  
Genetic Profiling ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Chinese Cohort ◽  
Thoracic Aneurysms ◽  
Genetic Profiles ◽  
Aortic Dissections

Abstract Background Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder for which 6 genes in the TGF-β pathway have been identified as causative. With the widespread use of genetic testing, the range of known clinical and genetic profiles has broadened, but these features have not been fully elucidated thus far. Methods and results Using gene panel sequencing or whole exome sequencing, we identified 54 unique rare variants in LDS genes in 57 patients with thoracic aneurysms/dissections, including 27 pathogenic mutations (P + LP) and 27 variants of unknown significance (VUSLP + VUS). Genotype-phenotype correlation analysis revealed that carriers with P/LP/ VUSLP variants in TGFBR1/TGFBR2/SMAD3 genes had significantly more severe cardiovascular features (cardiovascular death/dissection) than carriers with VUSs in these 3 genes at an early age and had less favorable event-free survival. Additionally, carriers with VUS in combination with other risk factors, such as hypertension, might be prone to developing an aortic dissection, as indicated by the fact that 5/8 (62.5%) patients with VUSs in our cohort developed aortic dissections in the presence of hypertension, compared with 25.0% (3/12) in the absence of hypertension (p = 0.047). Conclusions To date, this was the largest cohort of LDS patients ever reported in China, and the present study expanded the known mutation and phenotypic spectra of LDS, which might help refine our knowledge of LDS.

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