FGF14 encodes the fibroblast growth factor 14 protein that is primarily expressed in the brain, most abundantly in the cerebellum. FGF14 regulates spontaneous and evoked firing of Purkinje cells by interacting with and modulating the function of voltage-gated sodium channels at the axon initial segment. FGF14 contains a variable GAA repeat in intron 1 of its major isoform (isoform 1b). Expansion of the GAA repeat causes SCA27B (see Repeat s below), while coding point, frameshift, and structural variants in FGF14 cause SCA27A.
Repeat sizes:
• Normal: Range from 6 to 249 GAA repeats;
• Likely pathogenic (reduced penetrance): Range from 250 to 300 GAA repeats;
• Pathogenic (full penetrance): Range from > 300 GAA repeats.
The proposed mechanism underlying SCA27B is likely a loss of function via haploinsufficiency.
Molecular genetic testing
Molecular genetic testing relies on targeted analysis to characterize the and purity of the FGF14 GAA repeats. The diagnosis of SCA27B is established in a symptomatic individual with a compatible phenotype by the identification of a heterozygous (GAA)>300 repeat expansion in intron 1 of FGF14 by molecular genetic testing. Due to incomplete penetrance of FGF14 (GAA)250-300 repeat expansions, the diagnosis of SCA27B can also be established in symptomatic individuals with a (GAA)250-300 repeat expansion if their phenotype is compatible, other inherited causes of ataxia have been excluded, and, if possible, familial segregation with the disease is confirmed. Individuals whose phenotype differs significantly from SCA27B should be screened for other causes of inherited ataxias.
To date, pathogenic GAA repeat expansions in FGF14 cannot be reliably detected by standard sequence-based multigene panels, exome sequencing, or short-read genome sequencing.
Non-GAA-pure repeat expansions in FGF14 are likely not pathogenic for SCA27B when the total number of uninterrupted GAA repeats is below 250. Therefore, the molecular diagnosis of SCA27B relies on the accurate detection and establishment of both the and purity of the GAA repeat expansion.
Genotype-Phenotype Correlations
There is a weak inverse correlation between the age of onset and the of the GAA repeat expansion in some cohorts, but not all. Of note, one study found no association between disease progression or severity and the length of the GAA repeat expansion.
Biallelic FGF14 GAA repeat expansions have been reported in a number of individuals. In some – but not all – individuals with biallelic FGF14 GAA repeat expansions disease manifestations and progression appear to be more severe compared to individuals heterozygous for an FGF14 GAA repeat expansion.
Penetrance
Reduced penetrance has been reported in persons heterozygous for 250 to 300 FGF14 GAA repeats. Repeats of more than 300 GAA triplets appear to be fully penetrant. Non-GAA-pure expansions do not appear to cause ataxia, as no studies have yet shown segregation of non-GAA repeats with SCA27B. It is likely that knowledge of GAA repeat length-related penetrance will evolve significantly as more data become available.
Intergenerational instability
The FGF14 GAA repeat is highly unstable and almost always changes in upon parent to offspring transmission when the of parent’s GAA repeat expansion is greater than 75.
The of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
The instability of the GAA repeat locus upon maternal transmission, which is at high risk of further expansion, partly accounts for the high incidence of sporadic cases of SCA27B, whereby an unaffected mother transmits an expanded pathogenic allele to her offspring.
In contrast, contraction of the of the GAA repeat in the male germline may lead to transmission of reduced penetrance alleles to the offspring, resulting in “generation skipping” of the disease, thus presenting in a seemingly autosomal recessive manner. This differential transmission dynamic also likely accounts for the reduced male transmission of the disease observed in one study.
The degree of germline instability is proportional to the of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract. GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequences. During intergenerational transmission, pure GAA repeats have been shown to be more unstable than non-GAA-pure repeats.
FGF14