C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

2018 ◽  
Vol 18 (5-6) ◽  
pp. 239-253 ◽  
Author(s):  
Cristiane M. Ida ◽  
Malinda L. Butz ◽  
Patrick A. Lundquist ◽  
D. Brian Dawson
Keyword(s):  
Genetic Testing ◽  
Huntington Disease ◽  
Methylation Status ◽  
Repeat Expansion ◽  
Small Subset ◽  
C9orf72 Repeat Expansion ◽  
Specific Pcr ◽  
Status Assessment ◽  
Intermediate Alleles

Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.

scholarly journals Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines

2021 ◽  
Author(s):  
Ashley Scheiderer ◽  
Courtney Riedinger ◽  
Kristopher Kimball ◽  
Larry Kilgore ◽  
Amila Orucevic
Keyword(s):  
Genetic Testing ◽  
Endometrial Carcinoma ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Nuclear Staining ◽  
Mlh1 Promoter ◽  
History Of ◽  
The Times

Context.— The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. Objective.— To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. Design.— We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. Results.— Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. Conclusions.— Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

scholarly journals CDX2 methylation may predict the prognosis of patients with lung cancer

2021 ◽  
Author(s):  
Hongxue Cui ◽  
Zhenliang Zhang ◽  
Xueli Sun ◽  
Ling Fu ◽  
Xiaohua Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
Poor Prognosis ◽  
Cpg Island ◽  
Methylation Status ◽  
Prognostic Predictor ◽  
Specific Pcr ◽  
Kaplan Meier ◽  
Cox Analysis

IntroductionCDX2 methylation predicts poor prognosis in gastric cancer, squamous esophageal cancer and colorectal cancer. The present study was performed to investigate the roles of CDX2 methylation in lung cancer.Material and methodsOne hundred and sixty-seven patients with lung cancer were enrolled. Methylation-specific PCR (MSP) was performed to investigate the methylation status of CDX2. Sequencing of the CDX2 5’ CpG island was conducted as well. A 5-year follow-up was performed by a research nurse or dedicated physician. The primary endpoint was death related with lung cancer. Kaplan-Meier curve was used to analyze the survival situation of patients. Univariate and multivariate Cox analysis was performed to investigate the potential predictors for prognosis of patients with lung cancer.ResultsThe patients were classified into two groups according to CDX2 status: methylation (n=75) and unmethylation (n=92). After the 5-year follow-up, we found that the survival rate of patients with methylation of CDX2 was much lower than those with unmethylation of CDX2 (56% vs. 84.8%, P=0.000). Among the smoking patients, methylation of CDX2 was related with poorer prognosis of patients with lung cancer (P=0.000). DFS of patients with CDX2 methylation was lower than those without CDX2 methylation (56.0% vs. 73.9%, P=0.009). Univariate and multivariate Cox analysis demonstrated that CDX2 methylation served as independent prognostic predictor of patients with lung cancer (univariate: HR=3.705, 95%CI=1.922-7.139; multivariate: HR=3.418, 95%CI=1.826-6.397).ConclusionsCDX2 methylation may serve as independent prognostic predictor for patients with lung cancer.

SUV39H1-Mediated DNMT1 is Participated in the Epigenetic Regulation of Smad3 in Cervical Cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Li Zhang ◽  
Sijuan Tian ◽  
Minyi Zhao ◽  
Ting Yang ◽  
Shimin Quan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Lines ◽  
Epigenetic Regulation ◽  
Promoter Region ◽  
Methylation Status ◽  
Regulation Mechanism ◽  
Methylation Specific Pcr ◽  
Specific Pcr ◽  
Immune Factor ◽  
Cancer Tissues

Background: Smad3 is a pivotal intracellular mediator for participating in the activation of multiple immune signal pathway. Objective: The epigenetic regulation mechanism of the positive immune factor Smad3 in cervical cancer remains unknown. Therefore, the epigenetic regulation on Smad3 is investigated in this study. Methods: The methylation status of SMAD3 was detected by Methylation-specific PCR (MS-PCR) and Quantitative Methylation-specific PCR (MS-qPCR) in cervical cancer tissues and cell lines. The underlying molecular mechanisms of SUV39H1-DNMT1-Smad3 regulation was elucidated using cervical cancer cell lines containing siRNA or/and overexpression system. Confirmation of the regulation of DNMT1 by SUV39H1 used Chromatin immunoprecipitation-qPCR (ChIP-qPCR). The statistical methods used for comparing samples between groups were paired t tests and one-way ANOVAs. Results: H3K9me3 protein which regulated by SUV39H1 directly interacts with the DNMT1 promoter region to regulate its expression in cervical cancer cells, resulting in the reduce expression of the downstream target gene DNMT1. In addition, DNMT1 mediates the epigenetic modulation of the SMAD3 gene by directly binding to its promoter region. The depletion of DNMT1 effectively restores the expression of Smad3 in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1-DNMT1 was found to correlate with Smad3 expression in accordance with the expression at the cellular level. Notably, the promoter region of SMAD3 was hypermethylated in cervical cancer tissues, and this hypermethylation inhibits the subsequent gene expression. Conclusion: These results indicate that SUV39H1-DNMT1 is a crucial Smad3 regulatory axis in cervical cancer. SUV39H1-DNMT1 axis may provide a potential therapeutic target for the treatment of cervical cancer.

scholarly journals A framework for the evaluation of patients with congenital facial weakness

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bryn D. Webb ◽  
Irini Manoli ◽  
Elizabeth C. Engle ◽  
Ethylin W. Jabs
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
Patient Population ◽  
Clinical Care ◽  
Diagnostic Algorithm ◽  
Accurate Diagnosis ◽  
Facial Weakness ◽  
The Core ◽  
Follow Up Studies

AbstractThere is a broad differential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortunately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease specialists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care.

scholarly journals REscan: inferring repeat expansions and structural variation in paired-end short read sequencing data

2020 ◽  
Author(s):  
Russell Lewis McLaughlin
Keyword(s):  
Structural Variation ◽  
Sequence Data ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Sequencing Data ◽  
Short Read ◽  
Short Read Sequencing ◽  
Repeat Expansions ◽  
Paired End Sequencing

Abstract Motivation Repeat expansions are an important class of genetic variation in neurological diseases. However, the identification of novel repeat expansions using conventional sequencing methods is a challenge due to their typical lengths relative to short sequence reads and difficulty in producing accurate and unique alignments for repetitive sequence. However, this latter property can be harnessed in paired-end sequencing data to infer the possible locations of repeat expansions and other structural variation. Results This article presents REscan, a command-line utility that infers repeat expansion loci from paired-end short read sequencing data by reporting the proportion of reads orientated towards a locus that do not have an adequately mapped mate. A high REscan statistic relative to a population of data suggests a repeat expansion locus for experimental follow-up. This approach is validated using genome sequence data for 259 cases of amyotrophic lateral sclerosis, of which 24 are positive for a large repeat expansion in C9orf72, showing that REscan statistics readily discriminate repeat expansion carriers from non-carriers. Availabilityand implementation C source code at https://github.com/rlmcl/rescan (GNU General Public Licence v3).

scholarly journals Application of parallel stent placement in the treatment of unruptured vertebrobasilar fusiform aneurysms

2017 ◽  
Vol 126 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Jun Wang ◽  
Xin-Feng Liu ◽  
Bao-Min Li ◽  
Sheng Li ◽  
Xiang-Yu Cao ◽  
...  
Keyword(s):  
Stent Placement ◽  
Late Onset ◽  
Posterior Inferior Cerebellar Artery ◽  
Small Subset ◽  
Acceptable Result ◽  
Basilar Artery Thrombosis ◽  
Artery Thrombosis ◽  
Cerebellar Artery ◽  
Placement Technique

OBJECTIVE Large vertebrobasilar fusiform aneurysms (VFAs) represent a small subset of intracranial aneurysms and are often among the most difficult to treat. Current surgical and endovascular techniques fail to achieve a complete or acceptable result because of complications, including late-onset basilar artery thrombosis and perforator infarction. The parallel-stent placement technique was established in the authors' department, and this study reports the application of this technique in the treatment of unruptured VFAs. METHODS Eight patients with 8 unruptured VFAs who underwent parallel stent placement between April 2011 and August 2012 were included. The diameters of the VFAs ranged from 7.9 to 14.0 mm, and the lengths from 27.5 to 54.4 mm. Of the 8 patients with unruptured VFAs, 3 received double or triple parallel stents and 5 patients received a series-connected stent with another 1 or 2 stents deployed parallel to them. Outcomes for these patients were tabulated, based on the modified Rankin Scale (mRS) score and angiographic results. RESULTS All of the 25 stents were successfully placed without any treatment-related complications. During follow-up, 5 patients had decreased mRS scores, 2 were unchanged, and 1 was increased for subarachnoid hemorrhage. Immediate and follow-up clinical outcome was completely or partially recovered in most patients. Follow-up angiograms revealed 2 aneurysms were reduced in size and 6 were unchanged after stent placement. No in-stent stenosis, occlusion of the posterior inferior cerebellar artery, or perforators jailed by the stent occurred in any of the aneurysms. CONCLUSIONS These results provide encouraging support for the parallel-stent placement technique, which can be envisaged as an alternative strategy against unruptured VFAs. However, testing in more patients is needed.

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