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Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and...
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Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (1 February 2019) | Viewed by 38841

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Alisdair McNeill

E-Mail Website
Guest Editor
Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
Interests: neurogenetics; deep phenotyping; next generation sequencing; qualitative studies; rare disease

Special Issue Information

Dear Colleagues,

The contribution of genomic variants to the aetiopathogenesis of both paediatric and adult neurological disease is increasingly recognised. The use of next generation sequencing has led to the discovery of novel neurodevelopmental disorders, as exemplified by the Deciphering Developmental Disorders (DDD) study, and provided insight into the aetiopathogenesis of common adult neurological diseases. Despite these advances, many challenges remain. Correctly classifying the pathogenicity of genomic variants from amongst the large number of variants identified by next generation sequencing is recognised as perhaps the major challenge facing the field.  Deep phenotyping (e.g., imaging, movement analysis) techniques can aid variant interpretation by correctly classifying individuals as affected or unaffected for segregation studies. The lack of information on the clinical phenotype of novel genetic subtypes of neurological disease creates limitations for Genetic Counselling. Both deep phenotyping and qualitative studies can capture the clinical and patient’s perspective on a disease and provide valuable information. This Special Issue aims to highlight how next generation sequencing techniques have revolutionised our understanding of the aetiology of brain disease and describe the contribution of deep phenotyping studies to variant interpretation and understanding of natural history.   

Dr. Alisdair McNeill
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Next generation sequencing
  • Deep phenotyping
  • Neurogenetics
  • Rare disease

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

2 pages, 163 KiB  
Editorial
Editorial for Brain Sciences Special Issue: “Diagnosis of Neurogenetic Disorders: Contribution of Next-Generation Sequencing and Deep Phenotyping”
by Alisdair McNeill
Brain Sci. 2019, 9(3), 72; https://doi.org/10.3390/brainsci9030072 - 26 Mar 2019
Viewed by 2807
Abstract
In this Special Issue we bring together papers demonstrating the need for both detailed genomic and phenotypic studies to aid our scientific and clinical understanding of neurogenetic disorders [...] Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)

Research

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12 pages, 2216 KiB  
Article
Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
by Jennifer F. Gardner, Thomas D. Cushion, Georgios Niotakis, Heather E. Olson, P. Ellen Grant, Richard H. Scott, Neil Stoodley, Julie S. Cohen, Sakkubai Naidu, Tania Attie-Bitach, Maryse Bonnières, Lucile Boutaud, Férechté Encha-Razavi, Sheila M. Palmer-Smith, Hood Mugalaasi, Jonathan G. L. Mullins, Daniela T. Pilz and Andrew E. Fry
Brain Sci. 2018, 8(8), 145; https://doi.org/10.3390/brainsci8080145 - 7 Aug 2018
Cited by 17 | Viewed by 5640
Abstract
The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations [...] Read more.
The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations. Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)
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Review

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21 pages, 2171 KiB  
Review
The Role of Movement Analysis in Diagnosing and Monitoring Neurodegenerative Conditions: Insights from Gait and Postural Control
by Christopher Buckley, Lisa Alcock, Ríona McArdle, Rana Zia Ur Rehman, Silvia Del Din, Claudia Mazzà, Alison J. Yarnall and Lynn Rochester
Brain Sci. 2019, 9(2), 34; https://doi.org/10.3390/brainsci9020034 - 6 Feb 2019
Cited by 101 | Viewed by 10988
Abstract
Quantifying gait and postural control adds valuable information that aids in understanding neurological conditions where motor symptoms predominate and cause considerable functional impairment. Disease-specific clinical scales exist; however, they are often susceptible to subjectivity, and can lack sensitivity when identifying subtle gait and [...] Read more.
Quantifying gait and postural control adds valuable information that aids in understanding neurological conditions where motor symptoms predominate and cause considerable functional impairment. Disease-specific clinical scales exist; however, they are often susceptible to subjectivity, and can lack sensitivity when identifying subtle gait and postural impairments in prodromal cohorts and longitudinally to document disease progression. Numerous devices are available to objectively quantify a range of measurement outcomes pertaining to gait and postural control; however, efforts are required to standardise and harmonise approaches that are specific to the neurological condition and clinical assessment. Tools are urgently needed that address a number of unmet needs in neurological practice. Namely, these include timely and accurate diagnosis; disease stratification; risk prediction; tracking disease progression; and decision making for intervention optimisation and maximising therapeutic response (such as medication selection, disease staging, and targeted support). Using some recent examples of research across a range of relevant neurological conditions—including Parkinson’s disease, ataxia, and dementia—we will illustrate evidence that supports progress against these unmet clinical needs. We summarise the novel ‘big data’ approaches that utilise data mining and machine learning techniques to improve disease classification and risk prediction, and conclude with recommendations for future direction. Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)
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15 pages, 544 KiB  
Review
Parkinsonisms and Glucocerebrosidase Deficiency: A Comprehensive Review for Molecular and Cellular Mechanism of Glucocerebrosidase Deficiency
by Emilia M. Gatto, Gustavo Da Prat, Jose Luis Etcheverry, Guillermo Drelichman and Martin Cesarini
Brain Sci. 2019, 9(2), 30; https://doi.org/10.3390/brainsci9020030 - 1 Feb 2019
Cited by 15 | Viewed by 7342
Abstract
In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson’s disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our [...] Read more.
In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson’s disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (GBA) gene and PD. We conducted a review of this link, highlighting the association in GBA mutation carriers and in Gaucher disease type 1 patients (GD type 1). A comprehensive review of the literature from January 2008 to December 2018 was undertaken. Relevance findings include: (1) There is a bidirectional interaction between GBA and α- synuclein in protein homeostasis regulatory pathways involving the clearance of aggregated proteins. (2) The link between GBA deficiency and PD appears not to be restricted to α–synuclein aggregates but also involves Parkin and PINK1 mutations. (3) Other factors help explain this association, including early and later endosomes and the lysosomal-associated membrane protein 2A (LAMP-2A) involved in the chaperone-mediated autophagy (CMA). (4) The best knowledge allows researchers to explore new therapeutic pathways alongside substrate reduction or enzyme replacement therapies. Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)
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18 pages, 676 KiB  
Review
The Genetic Diagnosis of Neurodegenerative Diseases and Therapeutic Perspectives
by Julio-César García and Rosa-Helena Bustos
Brain Sci. 2018, 8(12), 222; https://doi.org/10.3390/brainsci8120222 - 13 Dec 2018
Cited by 24 | Viewed by 6323
Abstract
Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The [...] Read more.
Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The sequencing of candidate genes in patients suffering neurodegenerative pathologies is faster, more accurate, and has a lower cost, thereby enabling algorithms to be proposed regarding the risk of neurodegeneration onset in healthy persons including the year of onset and neurodegeneration severity. Next generation sequencing has resulted in an explosion of articles regarding the diagnosis of neurodegenerative diseases involving exome sequencing or sequencing a whole gene for correlating phenotypical expression with genetic mutations in proteins having key functions. Many of them occur in neuronal glia, which can trigger a proinflammatory effect leading to defective proteins causing sporadic or familial mutations. This article reviews the genetic diagnosis techniques and the importance of bioinformatics in interpreting results from neurodegenerative diseases. Risk scores must be established in the near future regarding diseases with a high incidence in healthy people for defining prevention strategies or an early start for giving drugs in the absence of symptoms. Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)
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Graphical abstract

15 pages, 738 KiB  
Review
Parkinson’s Disease and Metal Storage Disorders: A Systematic Review
by Edward Botsford, Jayan George and Ellen E. Buckley
Brain Sci. 2018, 8(11), 194; https://doi.org/10.3390/brainsci8110194 - 31 Oct 2018
Cited by 4 | Viewed by 4909
Abstract
Metal storage disorders (MSDs) are a set of rare inherited conditions with variable clinical pictures including neurological dysfunction. The objective of this study was, through a systematic review, to identify the prevalence of Parkinsonism in patients with MSDs in order to uncover novel [...] Read more.
Metal storage disorders (MSDs) are a set of rare inherited conditions with variable clinical pictures including neurological dysfunction. The objective of this study was, through a systematic review, to identify the prevalence of Parkinsonism in patients with MSDs in order to uncover novel pathways implemented in Parkinson’s disease. Human studies describing patients of any age with an MSD diagnosis were analysed. Foreign language publications as well as animal and cellular studies were excluded. Searches were conducted through PubMed and Ovid between April and September 2018. A total of 53 publications were identified including 43 case reports, nine cross-sectional studies, and one cohort study. The publication year ranged from 1981 to 2018. The most frequently identified MSDs were Pantothenate kinase-associated neurodegeneration (PKAN) with 11 papers describing Parkinsonism, Hereditary hemochromatosis (HH) (7 papers), and Wilson’s disease (6 papers). The mean ages of onset of Parkinsonism for these MSDs were 33, 53, and 48 years old, respectively. The Parkinsonian features described in the PKAN and HH patients were invariably atypical while the majority (4/6) of the Wilson’s disease papers had a typical picture. This paper has highlighted a relationship between MSDs and Parkinsonism. However, due to the low-level evidence identified, further research is required to better define what the relationship is. Full article
(This article belongs to the Special Issue Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping)
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