Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta-analysis

Clin Genet. 2021 Sep;100(3):258-267. doi: 10.1111/cge.13978. Epub 2021 May 27.

Abstract

Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta-analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22-repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.

Keywords: allele segregation; ancestral haplotypes; anticipation; fertility; meta-analysis; spinocerebellar ataxia type 2; unstable transmissions.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Age of Onset
  • Ataxin-2 / genetics*
  • Evolution, Molecular*
  • Genomic Instability
  • Haplotypes
  • Humans
  • Spinocerebellar Ataxias / genetics*
  • Trinucleotide Repeat Expansion*

Substances

  • ATXN2 protein, human
  • Ataxin-2