scholarly journals Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting

2020 ◽  
Vol 57 (8) ◽  
pp. 571-580
Author(s):  
Minghui Bao ◽  
Ping Li ◽  
Qifu Li ◽  
Hui Chen ◽  
Ying Zhong ◽  
...  
Keyword(s):  
Gene Product ◽  
Genetic Screening ◽  
Diagnostic Yield ◽  
Genetic Research ◽  
Functional Evaluation ◽  
Causative Gene ◽  
Gene Screening ◽  
Pathogenic Variants ◽  
Product Expression ◽  
Monogenic Hypertension

BackgroundMonogenic hypertension describe a series of hypertensive syndromes that are inherited by Mendelian laws. Sometimes genetic testing is required to provide evidence for their diagnoses, precise classification and targeted treatment. This study is the first to investigate the clinical utility of a causative gene screening and the combined yield of gene product expression analyses in cases with suspected monogenic hypertension.MethodsWe performed a large-scale multi-centre clinical genetic research of 1179 expertly selected hypertensive individuals from the Chinese Han population. Targeted sequencing were performed to evaluate 37 causative genes of potential cases of monogenic hypertension. Pathogenic and likely pathogenic variants were classified using the American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance (VUS) that had relatively high pathogenicity were selected and analysed using immunoblot protein expression assays.Results21 pathogenic or likely pathogenic variants were identified in 33 of 1179 cases (2.80%). Gene product expression analyses showed 27 VUSs harboured by 49 individuals (4.16%) could lead to abnormally expressed protein levels. Consequently, combining genetic screening with gene product expression analyses increased the diagnostic yield from 2.80% to 6.79%. The main aetiologies established were primary aldosteronism (PA; 27, 2.29%) and pheochromocytoma and paraganglioma (PPGL; 10, 0.85%).ConclusionMolecular diagnoses obtained using causative gene screening combined with gene product expression analyses initially achieved a modest diagnostic yield. Our data highlight the predominant roles of PA and PPGL. Furthermore, we provide evidence indicating the enhanced diagnostic ability of combined genetic and functional evaluation.

P3567Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Bao ◽  
J Zhong ◽  
J Cai ◽  
X Yang
Keyword(s):  
Functional Analysis ◽  
Diagnostic Yield ◽  
Basic Research ◽  
Functional Evaluation ◽  
Variants Of Unknown Significance ◽  
Treatment And Prevention ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Monogenic Hypertension ◽  
Number Of Individuals

Abstract Objectives Monogenic hypertension describes a series of hypertension syndromes inherited by Mendelian law and present with complex phenotypes. Methods 1179 cases with monogenic hypertension potential were evaluated by sequencing 37 causative genes. Pathogenic variants were classified by using American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance were selected to receive functional analysis. The yield of combined genetic and functional analysis was evaluated. Results 21 deleterious variants were identified in 33 of 1179 (2.80%). Functional analysis for 49 unknown significant variants showed 32 variants harbored by 61 individuals led to abnormally expressed protein levels. Overall, combining genetic screening with functional analysis promoted diagnostic yield to 8.73%. The main etiology established was primary aldosteronism, with CACNA1H harboring the greatest mutation burden. Logistic regression analysis showed hypertension complicated with special manifestations had the strongest correlation with disease causing variants detection (p=0.03). Sequencing Results Summary Number of variants Number of individuals* Percentage† Individuals with no variant 0 524 44.44% Individuals with variants identified 592 655 55.56% Individuals with single contributing variant 297 480 40.71% Individuals with two or multiple contributing variants 295 175 14.84% Number of variants identified   Pathogenic and likely pathogenic variants 21 33 2.80%   Variants of unknown significance 570 634 53.77%   Benign or likely benign variants 1 1 0.08% Type of variant   Frameshift deletion 8 15 1.27%   Frameshift insertion 5 5 0.42%   Nonframeshift deletion 10 10 0.85%   Nonframeshift insertion 6 12 1.02%   Nonsynonymous SNV 546 607 51.48%   Stopgain SNV 18 30 2.54% WES, whole-exome sequencing. *The statistics in this table was based on 1179 individuals. †The percentage was calculated by the number of individuals in each category. A flow chart of this study. Conclusion Our findings demonstrate an enhanced diagnostic ability by combining genetic analysis with functional evaluation and enables targeted treatment and prevention of hypertension. Acknowledgement/Funding This work was supported by National Basic Research Program of China (973 Program, 2014CB542300, 2014CB542302).

scholarly journals Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

2018 ◽  
Vol 4 (1) ◽  
pp. e212 ◽  
Author(s):  
Gloria T. Haskell ◽  
Michael C. Adams ◽  
Zheng Fan ◽  
Krunal Amin ◽  
Roberto J. Guzman Badillo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Gene List ◽  
Disease Genes ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Prior Testing ◽  
Genome Scale

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

scholarly journals Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Screening ◽  
Sanger Sequencing ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants ◽  
Case Summary ◽  
Heterozygous Carriers ◽  
Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

scholarly journals Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽  
2021 ◽  
Author(s):  
Chiara Cavestro ◽  
Celeste Panteghini ◽  
Chiara Reale ◽  
Alessia Nasca ◽  
Silvia Fenu ◽  
...  
Keyword(s):  
Early Onset ◽  
Cerebellar Atrophy ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Causative Gene ◽  
Coding Regions ◽  
Aberrant Transcript ◽  
Pathogenic Variants ◽  
Intronic Mutation ◽  
Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

2018 ◽  
Vol 90 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Ivo Eijkenboom ◽  
Maurice Sopacua ◽  
Janneke G J Hoeijmakers ◽  
Bianca T A de Greef ◽  
Patrick Lindsey ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Clinical Features ◽  
Genetic Screening ◽  
Clinical Genetic ◽  
Genetic Studies ◽  
Small Fibre Neuropathy ◽  
Reference Centre ◽  
Pathogenic Variants ◽  
Small Fibre ◽  
Genetic Science

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

T2042 Mismatch Repair Gene Product Expression and Colorectal Cancer in Hispanics

2008 ◽  
Vol 134 (4) ◽  
pp. A-606-A-607 ◽  
Author(s):  
Wilfredo E. De Jesus-Monge ◽  
Ronghua Zhao ◽  
Carmen Gonzalez-Keelan ◽  
Stanley R. Hamilton ◽  
Miguel Rodriguez-Bigas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Gene Product ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Product Expression

An immunohistochemical analysis of nm23 gene product expression in uveal melanoma

1997 ◽  
Vol 7 (3) ◽  
pp. 231-236 ◽  
Author(s):  
I M Greco ◽  
G Calvisi ◽  
L Ventura ◽  
F Cerrito
Keyword(s):  
Gene Product ◽  
Uveal Melanoma ◽  
Immunohistochemical Analysis ◽  
Product Expression ◽  
Nm23 Gene

scholarly journals Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Elias L. Salfati ◽  
Emily G. Spencer ◽  
Sarah E. Topol ◽  
Evan D. Muse ◽  
Manuel Rueda ◽  
...  
Keyword(s):  
Sudden Death ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Diagnostic ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

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