J Clin Neurol.  2018 Oct;14(4):498-504. 10.3988/jcn.2018.14.4.498.

A Novel Homozygous Variant of SETX Causes Ataxia with Oculomotor Apraxia Type 2

• Tariq H
• Imran R
• Naz S

• KMID: 2424178
• DOI: http://doi.org/10.3988/jcn.2018.14.4.498

Abstract

BACKGROUND AND PURPOSE
Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan.
METHODS
Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species.
RESULTS
Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases.
CONCLUSIONS
This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.

Keyword

ataxia; senataxin; Pakistan; ataxia-telangiectasia mutated; oculomotor apraxia; ataxia-telangiectasia; movement disorders

MeSH Terms

Alleles
Apraxias*
Ataxia Telangiectasia
Ataxia*
Cerebellar Ataxia
DNA
Exome
Genome
Humans
Magnetic Resonance Imaging
Movement Disorders
Mutation, Missense
Neurodegenerative Diseases
Pakistan
Phenotype
Population Characteristics
Spinocerebellar Ataxias
Vertebrates
DNA

Figure

• 

  Fig. 1 Pedigrees, MRI scans, and sequence analyses. A: Pedigree of family RDHT06. The genotypes for ATM c.7327 C>T (p.Arg2334Ter) are indicated below the symbols for the participants. Note that one unaffected individual (V:3) is homozygous for the variant and was asymptomatic. The arrow indicates the proband. B: Pedigree of family RDHT02. The genotypes for SETX c.212 C>T (p.Arg68Cys) are indicated below the symbols for all of the participants. The arrow indicates the proband. C: Axial brain T1-weighted MRI image showing vermian atrophy and atrophy of the cerebellar hemispheres, which is greater on the left side (indicated by an arrow). D: Axial brain MRI scan showing vermian atrophy and cystic dilation of the fourth ventricle, which is also observed in Dandy-Walker malformation (arrow). E: Sequence chromatograms of the respective parts of SETX indicating the wild-type allele in a normal control sample, the heterozygous pathogenic variant c.212 C>T (p.Arg68Cys) in an obligate carrier, and the homozygous missense mutation in an affected member. The arrow indicates the position of the mutation. F: Alignment of respective orthologues of SETX in different classes of vertebrates showing absolute conservation of p.Arg68 (boxed).

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