Unstable FGF14 GAA repeat expansions in Indian ataxia patients: a broader phenotype and involvement of modifier loci?

Spinocerebellar ataxia (SCA27B), due to an intronic GAA repeat expansion in the FGF14 gene, has been described recently. We screened DNA samples for expanded FGF14 GAA repeats in individuals with movement disorder (N = 526) in our laboratory at NIMHANS, Bengaluru, India. Clinically pathogenic repeat expansions of FGF14 (GAA) were detected in 14 of 526 patients (2.6%); seven with (GAA)_>300 repeats and seven with (GAA)_250-300 repeats. The classical downbeat nystagmus was seen in three patients. Four of the fourteen positive patients were symptomatic in early adulthood. A search for additional causative variants revealed two mutations. One patient with very early onset ataxia had a homozygous mutation (p.Arg199LeufsTer15) in the APTX ataxia gene, which is known to be involved in single-strand break repair. Another young patient who had developed symptoms at 11 years of age was heterozygous for a loss-of-function (p.Arg706*) allele in FAN1, a DNA modifier gene. Adaptive long-read sequencing of genomic DNA showed absence of a stabilising 17 bp sequence motif in expanded GAA alleles. Among healthy controls, 82% of alleles carried less than 25 GAA repeats, with (GAA)₉ being the most frequent allele. We also found intermediate-sized GAA expansions in 8.2% of ataxia patients. The clinical presentation in SCA27B patients is heterogeneous and may be modified by alleles at other loci. While the disease biology of each triplet repeat expansion disorder differs based on the gene product affected, there are many commonalities that might be important for treatment.