scholarly journals Amyotrophic Lateral Sclerosis Genetic Access Program

2021 ◽  
Vol 7 (5) ◽  
pp. e615
Author(s):  
Jennifer Roggenbuck ◽  
Kelly A. Rich ◽  
Leah Vicini ◽  
Marilly Palettas ◽  
Joceyln Schroeder ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Testing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Panel Testing ◽  
Hexanucleotide Repeat ◽  
Clinical Program ◽  
Access Program ◽  
Lateral Sclerosis

ObjectiveTo report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS).MethodsA multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP.ResultsA pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.ConclusionsThe ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.

scholarly journals Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria Babu ◽  
Filippo Favretto ◽  
Alain Ibáñez de Opakua ◽  
Marija Rankovic ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Folding ◽  
Neurodegenerative Diseases ◽  
Catalyst Activity ◽  
Coding Region ◽  
Prolyl Isomerase ◽  
X Ray Crystallography ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractAmyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.

scholarly journals Cancer Previvors in an Active Duty Service Women Population: An Opportunity for Prevention and Increased Force Readiness

2020 ◽  
Author(s):  
Leann A Lovejoy ◽  
Clesson E Turner ◽  
Craig D Shriver ◽  
Rachel E Ellsworth
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Cancer Predisposition ◽  
Clinical Genetic ◽  
High Risk Women ◽  
Clinical Genetic Testing ◽  
Pathogenic Mutations ◽  
History Of ◽  
Risk Reducing

Abstract Background The majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes (“previvors”) would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population. Methods The Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel. Results Of the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting. Discussion Within this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.

scholarly journals Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers

Oncotarget ◽  
2018 ◽  
Vol 9 (55) ◽  
pp. 30649-30660 ◽  
Author(s):  
Gloria H.J. Chan ◽  
Pei Yi Ong ◽  
Jeffrey J.H. Low ◽  
Hwai Loong Kong ◽  
Samuel G.W. Ow ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Gene Panel ◽  
Multiple Primary Cancers ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Asian Patients ◽  
Multiple Primary

scholarly journals Development of a Genomic DNA Reference Material Panel for Thalassemia Genetic Testing

2019 ◽  
Author(s):  
Zhen-Zhen Yin ◽  
Shou-Fang Qu ◽  
Chuan-Feng Huang ◽  
Fang Chen ◽  
Jian-Biao Li ◽  
...  
Keyword(s):  
Quality Assurance ◽  
Genetic Testing ◽  
Cell Lines ◽  
Reference Materials ◽  
Genomic Dna ◽  
Southern China ◽  
Testing Methods ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Technology Platforms

AbstractThalassemia is one of the most common autosomal recessive inherited diseases worldwide, and it is also highly prevalent and variable in Southern China. Various types of genetic testing technologies have been developed for diagnosis and screening of thalassemia. Characterized genomic DNA reference materials are necessary for assay development, validation, proficiency testing and quality assurance. However, there is no publicly available reference materials for thalassemia genetic testing as yet. To address the need for these materials, the National Institutes for Food and Drug Control and the China National Gene Bank established 31 new cell lines with 2 wild genotypes and 29 distinct genotypes of thalassemia which account for approximately 90% thalassemia carriers in China. The genomic DNA of 31 cell lines were characterized by four clinical genetic testing laboratories using different genetic testing methods and technology platforms. The genotyping results were concordant among four laboratories. In addition, the results of stability test demonstrated that the genotypes of these DNA samples were not influenced by preanalytical conditions such as long-term exposure to high temperature(37□) environment and repeated freeze-thawing. In conclusion, we developed the first national panel of 31 genomic DNA reference materials which are renewable and publicly available for the quality assurance of various genetic testing methods and will facilitate research and development in thalassemia genetic testing.

scholarly journals Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

2021 ◽  
Vol 4 (4) ◽  
pp. e202000764
Author(s):  
Arun Pal ◽  
Benedikt Kretner ◽  
Masin Abo-Rady ◽  
Hannes Glaβ ◽  
Banaja P Dash ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Repeat Expansions ◽  
Organelle Motility ◽  
Trafficking Defects ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

scholarly journals Patients with Amyotrophic Lateral Sclerosis Have High Interest in and Limited Access to Genetic Testing

2016 ◽  
Vol 26 (3) ◽  
pp. 604-611 ◽  
Author(s):  
Karin N. Wagner ◽  
Haikady Nagaraja ◽  
Dawn C. Allain ◽  
Adam Quick ◽  
Stephen Kolb ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Testing ◽  
Limited Access ◽  
High Interest ◽  
Lateral Sclerosis
Sign in / Sign up

Export Citation Format

Share Document