Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions

Abstract

Background: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability.

Methods: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor.

Findings: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA_250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA_250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA_≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r² = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r² = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees.

Interpretation: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA_250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling.

Funding: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Keywords: Diagnosis; GAA expansion; Hereditary cerebellar ataxia; SCA27B.

Fig. 1

Proportion of index patients with ataxia (black) (n = 845), and controls (gray) (n = 475) according to the size of their largest GAA repeat for FGF14. The proportion of carriers differed significantly above 300 GAA in patients (10.1%) compared to controls (1.1%) (p < 0.001; Fisher's test) as with <250 GAA whereas it was similar for GAA sizes between 250 and 299 GAA.

Fig. 2

Clinical features of patients with ataxia according to FGF14 GAA size groups (GAA_≥300 in red, GAA_250-299 in light orange, and GAA_<250 in dark blue). a: boxplot of the age at onset (the ends of the boxes are 25th and 75th percentiles, the middle line is the median, and the whiskers are 1.5 IQR; adjusted p-values after Kruskal–Wallis test). b: clinical features of SCA27B individuals with GAA_≥300 were similar to those with GAA sizes between 250 and 299 GAA (Fisher's test). c: the three key features of SCA27B which were significantly different in individuals with less than 250 GAA repeats (Fisher's test).

Fig. 3

Analysis of parent-offspring transmission of FGF14 GAA alleles according to the size of the expansion and sex of the transmitting parent (375 maternal transmissions in magenta and 255 paternal transmissions in turquoise). Transmission of alleles above 100 GAA showed instability with a maternal propensity to expand (p < 0.001; Kendall correlation test; r² = 0.42) versus a paternal tendency to contract (p < 0.001; Kendall correlation test; r² = 0.61).