Genetic basis of childhood-onset hereditary ataxias in Finland

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Ataxia involves incoordination of balance, gait, extremity movements, eye movements, and dysarthria. Hereditary ataxia has a heterogeneous genetic background, with hundreds of associated genes. Over the last decade, utilization of next-generation sequencing methods have become common, initially in a research setting and then in clinical use, allowing for analysis of all gene coding regions or a subset of genes at once instead of sequencing genes one-by-one in a selective manner. This has changed the diagnostic process for rare diseases, including hereditary ataxia, with faster identification of known disease-causing variants and description of novel ones. The aims of this study were to characterize the genetic causes of undiagnosed childhood ataxia in a Finnish cohort, identify novel genetic causes of ataxia, evaluate the diagnostic yield of exome sequencing for genetic diagnosis of hereditary childhood ataxia, and describe the genotype and phenotype of individuals with specific ataxias. In this study, exome sequencing and a genome-wide genotyping array were used to analyze the genetic background of children with ataxia. Patient medical records were reviewed and the severity of ataxia evaluated in a subset of individuals using the Scale for the Assessment and Rating of Ataxia clinical scale. In a cohort of 50 families with childhood-onset ataxia, the diagnostic yield of exome sequencing was 46% and approximately half of diagnosed families had a de novo variant. Using exome sequencing, causative variants were found in 18 different genes, including two novel ataxia genes, and 17 previously unpublished causative variants were identified. The heterogeneous genetic background of childhood-onset ataxia seen elsewhere in the world is reflected in our cohort and de novo variants explain a large proportion of this disease group. Two novel ataxia genes, SQSTM1 and GPAA1 were identified as part of two international collaborations. This work describes two novel diseases; a childhood-onset neurodegenerative disease with ataxia; caused by bi-allelic pathogenic variants in the gene SQSTM1 and developmental delay, epilepsy and cerebellar atrophy caused by bi-allelic pathogenic variants in the gene GPAA1. This thesis provides new information on phenotype and genetic mechanisms in a recently described neurodevelopmental disorder caused by variants in the transcription factor EBF3 and describes eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region that includes EBF3. After exome sequencing, nearly half of individuals with childhood-onset ataxia still remain without a genetic diagnosis. Emerging technologies including long-read sequencing and multi-omic strategies may help in the search of genetic variants overlooked by exome sequencing. However, periodic exome re-analysis has been shown to increase diagnostic yield and should be performed before applying additional and/or newer technologies. Although only few childhood-onset ataxias currently have treatments that affect the disease process, a genetic diagnosis has many benefits, including ending the laborious and stressful diagnostic odyssey, guiding management and giving prognosis; and aiding in family planning.
  • Lönnqvist, Tuula, Handledare
  • Isohanni, Pirjo, Handledare
  • Carroll, Christopher, Handledare
Tryckta ISBN978-951-51-7864-0
Elektroniska ISBN978-951-51-7865-7
StatusPublicerad - 2022
MoE-publikationstypG5 Doktorsavhandling (artikel)

Bibliografisk information

M1 - 94 s. + liitteet


  • 3123 Kvinno- och barnsjukdomar
  • 3112 Neurovetenskaper
  • 3124 Neurologi och psykiatri

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