TRIO gene segregation in a family with cerebellar ataxia

Rana Hanna Al Shaikh, Thomas Caulfield, Audrey J. Strongosky, Mavis Matthew, Karen R. Jansen-West, Mercedes Prudencio, John D. Fryer, Leonard Petrucelli, Ryan J. Uitti, Zbigniew K Wszolek

Research output: Contribution to journalArticle

Abstract

Aim of the study: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. Materials and methods: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). Results: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. Conclusions and clinical implications: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.

Original languageEnglish (US)
JournalNeurologia i Neurochirurgia Polska
DOIs
StateAccepted/In press - Jan 1 2018

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Cerebellar Ataxia
Ataxia
Genes
Mothers
Exome
Comparative Genomic Hybridization
Mitochondrial DNA
Spinocerebellar Ataxias
Phenotype
Mutation
Nuclear Family
Age of Onset
Exons
Genotype

Keywords

  • Cerebellum
  • Gait disorder/ataxia
  • Mental retardation
  • Spinocerebellar ataxia

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

TRIO gene segregation in a family with cerebellar ataxia. / Hanna Al Shaikh, Rana; Caulfield, Thomas; Strongosky, Audrey J.; Matthew, Mavis; Jansen-West, Karen R.; Prudencio, Mercedes; Fryer, John D.; Petrucelli, Leonard; Uitti, Ryan J.; Wszolek, Zbigniew K.

In: Neurologia i Neurochirurgia Polska, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Aim of the study: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. Materials and methods: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). Results: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. Conclusions and clinical implications: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.",
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AU - Strongosky, Audrey J.

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AU - Jansen-West, Karen R.

AU - Prudencio, Mercedes

AU - Fryer, John D.

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AU - Uitti, Ryan J.

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AB - Aim of the study: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. Materials and methods: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). Results: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. Conclusions and clinical implications: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.

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