Special Issue "Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping"

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Clinical Neuroscience".

Deadline for manuscript submissions: 1 February 2019

Special Issue Editor

Guest Editor
Dr. Alisdair McNeill

Senior Clinical Research Fellow, Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
Honrorary Consultant in Clinical Genetics, Sheffield Children’s NHS Foundation Trust
Website | E-Mail
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

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Keywords

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

Published Papers (3 papers)

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Research

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Open AccessArticle Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
Brain Sci. 2018, 8(8), 145; https://doi.org/10.3390/brainsci8080145
Received: 30 May 2018 / Revised: 6 July 2018 / Accepted: 17 July 2018 / Published: 7 August 2018
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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
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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
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Review

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Open AccessReview The Genetic Diagnosis of Neurodegenerative Diseases and Therapeutic Perspectives
Brain Sci. 2018, 8(12), 222; https://doi.org/10.3390/brainsci8120222
Received: 11 October 2018 / Revised: 26 November 2018 / Accepted: 7 December 2018 / Published: 13 December 2018
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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
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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
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Open AccessReview Parkinson’s Disease and Metal Storage Disorders: A Systematic Review
Brain Sci. 2018, 8(11), 194; https://doi.org/10.3390/brainsci8110194
Received: 9 October 2018 / Revised: 29 October 2018 / Accepted: 30 October 2018 / Published: 31 October 2018
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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
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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
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