Genetic counselling and testing for neurodegenerative disorders using a proposed standard of practice for ALS/MND: diagnostic testing comes first

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.

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Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important

Journal of Molecular Medicine ◽

10.1007/s00109-020-01966-z ◽

2020 ◽

Vol 98 (10) ◽

pp. 1447-1455 ◽

Cited By ~ 1

Author(s):

Thomas Eggermann ◽

Johanna Brück ◽

Cordula Knopp ◽

György Fekete ◽

Christian Kratz ◽

...

Keyword(s):

Genetic Counselling ◽

Molecular Diagnosis ◽

Broad Spectrum ◽

Clinical Management ◽

Diagnostic Testing ◽

Molecular Diagnostic ◽

List Type ◽

Molecular Defects ◽

Molecular Alterations ◽

Silver Russell Syndrome

Abstract Molecular diagnostic testing of the 11p15.5-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging due to the broad spectrum of molecular defects and their mosaic occurrence. Additionally, the decision on the molecular testing algorithm is hindered by their clinical heterogeneity. However, the precise identification of the type of defect is often a prerequisite for the clinical management and genetic counselling. Four major molecular alterations (epimutations, uniparental disomies, copy number variants, single nucleotide variants) have been identified, but their frequencies vary between SRS and BWS. Due to their molecular aetiology, epimutations in both disorders as well as upd(11)pat in BWS are particular prone to mosaicism which might additionally complicate the interpretation of testing results. We report on our experience of molecular analysis in a total cohort of 1448 patients referred for diagnostic testing of BWS and SRS, comprising a dataset from 737 new patients and from 711 cases from a recent study. Though the majority of positively tested patients showed the expected molecular results, we identified a considerable number of clinically unexpected molecular alterations as well as not yet reported changes and discrepant mosaic distributions. Additionally, the rate of multilocus imprinting disturbances among the patients with epimutations and uniparental diploidies could be further specified. Altogether, these cases show that comprehensive testing strategies have to be applied in diagnostic testing of SRS and BWS. The precise molecular diagnosis is required as the basis for a targeted management (e.g. ECG (electrocardiogram) and tumour surveillance in BWS, growth treatment in SRS). The molecular diagnosis furthermore provides the basis for genetic counselling. However, it has to be considered that recurrence risk calculation is determined by the phenotypic consequences of each molecular alteration and mechanism by which the alteration arose. Key messages The detection rates for the typical molecular defects of Beckwith-Wiedemann syndrome or Silver-Russell syndrome (BWS, SRS) are lower in routine cohorts than in clinically well-characterised ones. A broad spectrum of (unexpected) molecular alterations in both disorders can be identified. Multilocus imprinting disturbances (MLID) are less frequent in SRS than expected. The frequency of MLID and uniparental diploidy in BWS is confirmed. Mosaicism is a diagnostic challenge in BWS and SRS. The precise determination of the molecular defects affecting is the basis for a targeted clinical management and genetic counselling.

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Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders

Journal of Personalized Medicine ◽

10.3390/jpm11060474 ◽

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.

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Imprinting centre deletions in two PWS families: implications for diagnostic testing and genetic counselling

Clinical Genetics ◽

10.1034/j.1399-0004.2000.580406.x ◽

2001 ◽

Vol 58 (4) ◽

pp. 284-290 ◽

Cited By ~ 22

Author(s):

K Buiting ◽

C Färber ◽

P Kroisel ◽

K Wagner ◽

L Brueton ◽

...

Keyword(s):

Genetic Counselling ◽

Diagnostic Testing

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Insights into amyloid disease from fly models

Essays in Biochemistry ◽

10.1042/bse0560069 ◽

2014 ◽

Vol 56 ◽

pp. 69-83 ◽

Cited By ~ 1

Author(s):

Ko-Fan Chen ◽

Damian C. Crowther

Keyword(s):

Drosophila Melanogaster ◽

Neurodegenerative Disorders ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Disease Pathogenesis ◽

Amyloid Aggregates ◽

Aβ Amyloid ◽

Polypeptide Chains ◽

Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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Gastroesophageal Reflux Disease: A Gastroenterologist's Perspective

Perspectives on Voice and Voice Disorders ◽

10.1044/vvd21.3.89 ◽

2011 ◽

Vol 21 (3) ◽

pp. 89-99

Author(s):

Michael F. Vaezi

Keyword(s):

Gastroesophageal Reflux Disease ◽

Gastroesophageal Reflux ◽

Reflux Disease ◽

Best Practice ◽

Clinical Care ◽

Diagnostic Testing ◽

Diagnostic Tools ◽

Swallowing Function ◽

Atypical Symptoms

Gastroesophageal reflux disease (GERD) is a commonly diagnosed condition often associated with the typical symptoms of heartburn and regurgitation, although it may present with atypical symptoms such as chest pain, hoarseness, chronic cough, and asthma. In most cases, the patient's reduced quality of life drives clinical care and diagnostic testing. Because of its widespread impact on voice and swallowing function as well as its social implications, it is important that speech-language pathologists (SLPs) understand the nature of GERD and its consequences. The purpose of this article is to summarize the nature of GERD and GERD-related complications such as GERD-related peptic stricture, Barrett's esophagus and adenocarcinoma, and laryngeal manifestations of GERD from a gastroenterologist's perspective. It is critical that SLPs who work with a multidisciplinary team understand terminology, diagnostic tools, and treatment to ensure best practice.

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