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Monogenic causes of neurological movement disorders - a case study of a family with hereditary ataxia

Kafantari, Efthymia (2019) BINP51 20181
Degree Projects in Bioinformatics
Popular Abstract
Monogenic causes of movement disorders. A case study of a family with ataxia.

Movement disorders constitute a group of neurological conditions and syndromes which mainly lead to abnormal motor functions. In case of ataxias, numerous of underling etiologies have been elucidated. Hereditary ataxias cannot be classified easily, due to the heterogeneity and nondistinct phenotypes. For autosomal recessive hereditary ataxias (ARA), mutations on a large number of genes have been incriminated to cause the condition but in most cases, causative variants were identified in only a small number of affected individuals. Therefore, for the diagnosis of ARA a comprehensive approach like whole exome sequencing (WES) is mostly preferable as both known... (More)
Monogenic causes of movement disorders. A case study of a family with ataxia.

Movement disorders constitute a group of neurological conditions and syndromes which mainly lead to abnormal motor functions. In case of ataxias, numerous of underling etiologies have been elucidated. Hereditary ataxias cannot be classified easily, due to the heterogeneity and nondistinct phenotypes. For autosomal recessive hereditary ataxias (ARA), mutations on a large number of genes have been incriminated to cause the condition but in most cases, causative variants were identified in only a small number of affected individuals. Therefore, for the diagnosis of ARA a comprehensive approach like whole exome sequencing (WES) is mostly preferable as both known and novel variants can be detected.

In this project, a family with affected members with ataxia and a markedly reduced volume of cerebellar structures was analyzed. The aim was to identify the disease-causative variant (in case of homozygosity) or variants (in case of compound heterozygosity) that co-segregate with hereditary ataxia in this family and is inherited in an autosomal recessive manner.

From the obtained mapped BAM files generated after Ion Torrent sequencing all the family members (two affected siblings, the father, the mother and the one unaffected sibling), Variant Calling Format (VCF) files were generated by using two different tools, Ion Torrent-Variant Caller and Genome Analysis Toolkit (GATK) in combination with additional algorithms. The VCF files were then annotated with Variant Effect Predictor (VEP). A filtering out strategy was followed based on the quality criteria of VCF files, minor allele frequencies (MAFs) of the variants, consequences of the variants on the gene product and the mode of inheritance. The list of candidate variants that emerged was further narrowed down based on predicted pathogenicity and conservation scores and on the MAF of the variants according to the prevalence of the condition in the General and European populations.

Only one variant remained as a candidate, the rs145790279 of the NBPF3 gene. Further investigation by using web tools, reveal that the glutamic acid residue of the protein sequence that is substituted, is located in a coiled coil motif where these residues seem to be well conserved and not prone to substitutions. Moreover, NBPF3 protein contains tandemly repeat copies of DUF1220 domains which have been implicated in brain-size pathology. In addition, according to experimental evidence, NBPF3 interacts with TSEN15 subunit of tRNA splicing endonuclease, which is associated with Pontocerebellar hypoplasia (PCH), a group of neurodevelopmental disorders which share some common symptoms with spinocerebellar ataxias. According to guidelines for variant classification, these findings constitute moderate and supporting evidence of the variant’s pathogenicity. On the other hand, the fact that the variant is not very rare in the population or absent from databases with known variants, (something that it is expected as each ARA separately is considered as a very rare disorder), contradicts the above evidence. Therefore, the variant is classified as of uncertain significance. However, as the structure and function of the protein is not well characterized, it is suggested that further computational analysis on a protein level, in order to investigate its structure and interaction with the TSEN15 protein, would be worthwhile.


Master’s degree project in Bioinformatics 45 credits, 2019
Department of Biology, Lund University

Advisors: Dr. Andreas Puschmann/Dr. Björn Canbäck
Department for Neurology, Lund University Hospital/Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Kafantari, Efthymia
supervisor
organization
course
BINP51 20181
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8975183
date added to LUP
2019-05-08 15:52:15
date last changed
2019-05-08 15:52:15
@misc{8975183,
  author       = {{Kafantari, Efthymia}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Monogenic causes of neurological movement disorders - a case study of a family with hereditary ataxia}},
  year         = {{2019}},
}