Special Issue "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: 5 November 2018

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 (1 paper)

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Research

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
PDF Full-text (2216 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
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