Genetic and Phenotypic Variability in Siblings With Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by FXN gene mutations involving GAA trinucleotide repeat expansions. This study explores phenotypic heterogeneity between siblings, focusing on differences in age at onset (AAO) and shorter GAA repeat (GAA1) length to improve understanding of disease variability.

We analyzed AAO and genotype of siblings with FRDA. Linear regression examined AAO differences and genetic predictors (GAA1 length and SIRT6 S46N single nucleotide polymorphism), while logistic regression assessed discordant clinical manifestations and GAA1 heterogeneity.

This study included 150 siblings with FRDA from 70 families. GAA1 and AAO differences between siblings were not significant, although discordance between siblings in the diagnosis of hypertrophic cardiomyopathy and scoliosis was noted in approximately a quarter of the families. Differences in GAA1 length predicted a modest amount of AAO heterogeneity (R² = 0.075). The S46N polymorphism in SIRT6 did not predict the differences in AAO.

Genetic and phenotypic variability between paired siblings with FRDA was moderate to small, with GAA1 differences explaining some of the variance in AAO. Other factors (genetic or environmental) or data collection bias may explain the remaining variance. These findings highlight the complexity of FRDA and reiterate the role of GAA1 length in disease severity.