scholarly journals Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders

2021 ◽  
Vol 11 (6) ◽  
pp. 474
Author(s):  
Stefania Zampatti ◽  
Michele Ragazzo ◽  
Cristina Peconi ◽  
Serena Luciano ◽  
Stefano Gambardella ◽  
...  
Keyword(s):  
Genetic Counselling ◽  
Neurodegenerative Disorders ◽  
Genetic Variants ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Small Time ◽  
Molecular Characterisation ◽  
Dementia Patients ◽  
Phenotypic Characterisation ◽  
Dementing Disorders

Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.

Optimal Genetic Screening for Cystic Fibrosis

2021 ◽  
Author(s):  
Hussein El Hajj ◽  
Douglas R. Bish ◽  
Ebru K. Bish
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Genetic Screening ◽  
Genetic Diseases ◽  
The United States ◽  
Published Data ◽  
Decision Support Model ◽  
Screening Process ◽  
Public Health Initiative ◽  
Cystic Fibrosis Screening

Improving Newborn Screening for Genetic Diseases Screening newborns for life-threatening genetic diseases is an important public health initiative. Cystic fibrosis is one of the most prevalent diseases in this context. As part of the cystic fibrosis screening process, all states in the United States use multiple tests, including genetic tests that detect a subset of the more than 300 genetic variants (specific mutations) that cause cystic fibrosis. In “Optimal Genetic Screening for Cystic Fibrosis,” El-Hajj, D.R. Bish, and E.K. Bish develop a decision support model to select which genetic variants to screen for, considering the trade-off between classification accuracy and testing cost, and the technological constraints that limit the number of variants selected. Because variant prevalence rates are highly uncertain, a robust optimization framework is developed. Further, two commonly used cystic fibrosis screening processes are analytically compared, and conditions under which each process dominates are established. A case study based on published data are provided.

Perspectives on Allele-Specific Expression

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Siobhan Cleary ◽  
Cathal Seoighe
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Data Science ◽  
Genetic Diseases ◽  
Annual Review ◽  
Publication Date ◽  
Biomedical Data ◽  
Specific Expression ◽  
Cis Acting ◽  
Gene Copies

Diploidy has profound implications for population genetics and susceptibility to genetic diseases. Although two copies are present for most genes in the human genome, they are not necessarily both active or active at the same level in a given individual. Genomic imprinting, resulting in exclusive or biased expression in favor of the allele of paternal or maternal origin, is now believed to affect hundreds of human genes. A far greater number of genes display unequal expression of gene copies due to cis-acting genetic variants that perturb gene expression. The availability of data generated by RNA sequencing applied to large numbers of individuals and tissue types has generated unprecedented opportunities to assess the contribution of genetic variation to allelic imbalance in gene expression. Here we review the insights gained through the analysis of these data about the extent of the genetic contribution to allelic expression imbalance, the tools and statistical models for gene expression imbalance, and what the results obtained reveal about the contribution of genetic variants that alter gene expression to complex human diseases and phenotypes. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 4 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

2019 ◽  
Author(s):  
Go Hun Seo ◽  
Taeho Kim ◽  
Jung-young Park ◽  
Jungsul Lee ◽  
Sehwan Kim ◽  
...  
Keyword(s):  
Family Member ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Whole Exome ◽  
Interpretation System ◽  
Automated Interpretation ◽  
Age Range

AbstractPurposeEVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders.MethodsDNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to WES. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments.ResultsThe average number of overlapping organ categories per patient was 4.5 ± 5.0. EVIDENCE reported a total 244 variants in 215 (65.1%) of the 330 probands. After clinical reassessment and/or family member testing, 196 variants were identified in 171 probands (51.8%), including 115 novel variants. These variants were confirmed as being responsible for 146 genetic disorders. One hundred-seven (54.6%) of the 196 variants were categorized as pathogenic or likely pathogenic before, and 146 (74.6%) after, clinical assessment and/or family member testing. Factors associated with a variant being confirmed as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores between that variant and a patient’s phenotype.ConclusionThis new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 51% improvement in diagnostic yield.

scholarly journals Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia

2020 ◽  
Vol 295 (52) ◽  
pp. 18508-18523
Author(s):  
Nora Lemke ◽  
Valeria Melis ◽  
Dilyara Lauer ◽  
Mandy Magbagbeolu ◽  
Boris Neumann ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Genetic Variants ◽  
Subcellular Fractionation ◽  
Brain Regions ◽  
Transgenic Mouse Model ◽  
Protein Species ◽  
Synapse Loss ◽  
Triton X

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

scholarly journals Spectrum of desmosomal gene variations in patients with arrhythmogenic right ventricular cardiomyopathy

2021 ◽  
Vol 26 (10) ◽  
pp. 4692
Author(s):  
A. G. Shestak ◽  
O. V. Blagova ◽  
Yu. A. Lutokhina ◽  
S. L. Dzemeshkevich ◽  
E. V. Zaklyazminskaya
Keyword(s):  
Right Ventricular ◽  
Genetic Variants ◽  
Diagnostic Yield ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Severe Disease ◽  
Positive Family History ◽  
Gene Mutations ◽  
Ventricular Cardiomyopathy ◽  
Detection Of Mutations ◽  
Class Iv

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary myocardial disease with a high risk of sudden cardiac death. The most common genetic forms of the disease are associated with desmosomal gene mutations.Aim. To study the prevalence of desmosomal forms of ARVC and to analyze variations in the PKP2, DSG2, DSP, DSC2 and JUP genes in a sample of Russian patients with ARVC.Material and methods. Included patients with ARVC underwent resting electrocardiography (ECG), 24-hour Holter ECG monitoring, echocardiography, chest x-ray, myocardial biopsy (if indicated), contrast-enhanced cardiac magnetic resonance imaging. All patients underwent medical genetic counseling. Mutations in the PKP2, DSG2, DSP, DSC2, and JUP genes was detected using highthroughput sequencing on the IonTorrent platform, followed by Sanger sequencing of uncovered gene regions. The pathogenicity of identified genetic variations was assessed according to modern guidelines.Results. ARVC was established in 80 Russian unrelated patients. More than half of the probands (57%) in the study sample had definite diagnosis of ARVC, while 30% and 13% — borderline and possible ARVC, respectively. A positive family history of heart disease and/or SCD was noted in 30%. Genetic variants of pathogenicity class IV-V were detected in 15 (18,75%) probands in the PKP2, DSG2, DSP genes. The detection of genetic variants of pathogenicity class IV-V was different in the subgroups of patients with varying degrees of diagnosis reliability: 13 probands (28,3%) in the subgroup with definite ARVC and 2 probands (8,3%) in the subgroup with borderline ARVC. No genotype-positive probands were found in the subgroup with possible ARVC. Variations of unknown clinical significance were found in 13 (16,25%) probands.Conclusion. The diagnostic yield of the desmosomal genes PKP2, DSG2, DSP, DSC2, and JUP was 19% with initial diagnosis of ARVC. The detection of mutations was significantly higher in patients with definite ARVC and severe disease manifestations.

scholarly journals The contribution of common regulatory and protein-coding TYR variants in the genetic architecture of albinism

2021 ◽  
Author(s):  
Vincent Michaud ◽  
Eulalie Lasseaux ◽  
David J Green ◽  
Dave T Gerrard ◽  
Claudio Plaisant ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Large Scale ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Gene Encoding ◽  
Protein Coding ◽  
Autosomal Recessive Disorders ◽  
Functional Variants ◽  
Prevalent Disease ◽  
Coding Variants

Genetic diseases have been historically segregated into rare Mendelian and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. We studied a cohort of 1,313 individuals with albinism aiming to gain insights into the genetic architecture of rare, autosomal recessive disorders. We investigated the contribution of regulatory and protein-coding variants at the common and rare ends of the allele-frequency spectrum. We focused on TYR, the gene encoding tyrosinase, and found that a promoter variant, TYR: c.-301C>T [rs4547091], modulates the penetrance of a prevalent, disease-associated missense change, TYR: c.1205G>A [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functional variants, TYR: c.[-301C;575C>A;1205G>A], confers a high risk of albinism (OR>77) and is associated with reduced vision in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.

scholarly journals Elucidating the genetic basis of an oligogenic birth defect using whole genome sequence data in a non-model organism, Bubalus bubalis

2016 ◽  
Author(s):  
Lynsey K. Whitacre ◽  
Jesse L. Hoff ◽  
Robert D. Schnabel ◽  
Sara Albarella ◽  
Francesca Ciotola ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Water Buffalo ◽  
Genetic Diseases ◽  
Modifier Genes ◽  
Whole Genome ◽  
Disease Phenotype ◽  
Inheritance Pattern ◽  
Strong Selection ◽  
Severity Of The Disease ◽  
Mode Of Inheritance

AbstractRecent strong selection for dairy traits in water buffalo has been associated with higher levels of inbreeding, leading to an increase in the prevalence of genetic diseases such as transverse hemimelia (TH), a congenital developmental abnormality characterized by the absence of a variable distal portion of the hindlimbs. The limited genomic resources available for water buffalo, in conjunction with an unconfirmed inheritance pattern, required an original approach to identify genetic variants associated with this disease. The genomes of 4 bilaterally affected cases, 7 unilaterally affected cases, and 14 controls were sequenced. Variant calling identified 19.8 million high confidence single nucleotide polymorphisms (SNPs) and 2.8 million insertions/deletions (INDELs). A concordance analysis of SNPs and INDELs requiring all unilateral and bilateral cases and none of the controls to be homozygous for the same allele, revealed two genes, WNT7A and SMARCA4, known to play a role in embryonic hindlimb development. Additionally, SNP alleles in NOTCH1 and RARB were homozygous exclusively in the bilaterally affected cases, suggesting an oligogenic mode of inheritance. Homozygosity mapping by whole genome de novo assembly was then used to identify large contigs representing regions of homozygosity in the cases. This also supported an oligogenic mode of inheritance; implicating 13 genes involved in aberrant hindlimb development in the bilateral cases and 11 in the unilateral cases. A genome-wide association study (GWAS) predicted additional modifier genes. Results from these analyses suggest that mutations in SMARCA4 and WNT7A are required for expression of TH, while several other loci including NOTCH1 act as modifiers and increase the severity of the disease phenotype. Although our data show that the inheritance of TH is complex, we predict that homozygous variants in WNT7A and SMARCA4 are necessary for the expression of TH and selection against these variants and avoidance of carrier-to-carrier matings should eradicate TH.Author SummaryGenetic diseases often occur and are spread through small populations under strong selection where rates of inbreeding can be significant. The use of a limited number of water buffalo males via artificial insemination for genetic improvement of milk and milk composition has increased the frequency of the genetic disease, transverse hemimelia (TH). Transverse hemimelia affected calves are normally developed except for malformation of one or both hindlimbs or both hindlimbs and one or both forelimbs. Little is known about the inheritance pattern of TH. We discovered genetic variants present in cases where both hindlimbs and one forelimb were affected, cases were both hindlimbs were affected, cases where only one hindlimb was affected, and in non-affected water buffalo that predict TH to be inherited as an oligogenic disease with two driver loci necessary for disease expression and several additional modifier genes that are responsible for the severity of the disease phenotype. We predict that selection against mutations in the two major loci and the avoidance of mating animals that are heterozygous for these mutations will eliminate TH from water buffalo.

Genetic testing services in Europe: Quality assurance and policy issues

2001 ◽  
Vol 8 (2) ◽  
Author(s):  
Jean-Jacques Cassiman ◽  
Alastair Kent ◽  
Glenn Miller ◽  
Peter Miny ◽  
Erik Tambuyzer
Keyword(s):  
Quality Assurance ◽  
Genetic Testing ◽  
Science Fiction ◽  
Genetic Counselling ◽  
Genetic Diseases ◽  
Molecular Genetic ◽  
Diagnostic Testing ◽  
Dna Profile ◽  
Patient Groups

The popular press is painting a picture of a future in which everyone has a detailed DNA profile of themselves drawn up. Such a vision of the future, however, is more science fiction than science practice. Predictive tests for complex diseases and cancer, eg colon cancer and breast cancer, are increasingly being used, and the related, and important, genetic counselling may become complex and comprehensive. Quality assurance in genetic testing for both cytogenetics and molecular genetic testing in Europe is also described. The quality of genetic testing in Europe could be substantially improved, and before a genetic test is accepted as a routine diagnostic or prognostic procedure it should have proven clinical utility. Pharmacogenetic testing looks at the efficacy of medicines and their side effects on patients and patient groups, and is increasingly being used to develop better targeted medicines. Genetic testing services and genetic counselling are structured in different ways in Europe, and organisation and reimbursement differ among European countries. Quality and non-directive genetic counselling must be made an integral part of quality genetic testing services, and be sufficiently reimbursed. European networking and identification of reference centres for quality-based diagnostic testing of genetic diseases should be encouraged. Reimbursement within Europe for sample forwarding should be adapted to allow samples to be tested in countries other than the country of origin of the patient.

scholarly journals Spirituality and Self-Efficacy in Caregivers of Patients with Neurodegenerative Disorders: An Overview of Spiritual Coping Styles

Religions ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 276 ◽  
Author(s):  
Juan González-Rivera ◽  
Adam Rosario-Rodríguez
Keyword(s):  
Mental Health ◽  
Neurodegenerative Disorders ◽  
Self Efficacy ◽  
Coping Style ◽  
Neurodegenerative Disorder ◽  
Coping Styles ◽  
Spiritual Coping ◽  
Psychological Resources ◽  
Face To Face ◽  
Dementia Patients

The objective of this research was to assess the effect of spirituality and self-efficacy in the mental health of caregivers of patients with neurodegenerative disorders. Four styles of spiritual coping were examined to identify which of them can function as protective or risk factors for caregivers of patients with neurodegenerative disorders. Interviews were conducted face-to-face to 116 caregivers of patients diagnosed with some type of neurodegenerative disorder. The results showed that caregivers with a selfless spiritual coping style exhibit significantly higher depression, stress, and perceived overload than those with a collaborative style. No statistically significant differences were found between the means of the other styles of spiritual coping. Simultaneously, it was found that the selfless spiritual coping style is a risk factor for overload, depression, and stress. The study is a first step in understanding how spirituality interacts with self-efficacy to protect the mental health of caregivers of dementia patients in Puerto Rico. Our results theoretically and empirically support the functional compatibility of both psychological resources.

Sign in / Sign up

Export Citation Format

Share Document