Hereditary neuropathy or pain disorder

STR: FGF14_TTC

Green List (high evidence)

The name of this STR has been changed from FGF14_GAA to FGF14_TTC as FGF14 is transcribed from the reverse strand of the sequence.
The coordinates for the repeated sequence have been updated to those shown in https://stripy.org/database/FGF14. Previously, the coordinates were for the whole gene, rather than the repeated sequence.

Created: 11 Mar 2025, 11:18 a.m. | Last Modified: 11 Mar 2025, 11:18 a.m.

Panel Version: 6.162

FGF14_GAA added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.

Created: 21 Oct 2024, 3:35 p.m. | Last Modified: 21 Oct 2024, 3:35 p.m.

Panel Version: 5.22

Comment on list classification: FGF14_GAA is not currently reportable, as the coordinates are not present on the analysis pipeline.

Created: 21 Oct 2024, 3:27 p.m. | Last Modified: 21 Oct 2024, 3:27 p.m.

Panel Version: 5.22

After NHS Genomic Medicine Service consideration, the rating of this STR has not been changed and remains Amber.

Comments from review:
Agree that the expansion is likely disease causing. However only a small number of cases have been used to define the number of repeats that could be considered pathogenic. Would recommend that more cases should be identified to better define the pathogenic repeat lengths of this STR. Perhaps study in 100,000 Genomes and GMS data would provide additional cases.

Agree that alleles >250 rpts are of interest and those >300 likely to be diagnostic but concerned that Expansion Hunter will not be able to provide accurate sizing beyond a threshold well below this (~100 repeats). See Supplementary figure S2 of PMID 36493768 for an illustration of this. Can ExpansionHunterDeNovo do better using paired IRRs (PMID PMID: 32345345), or can Expansion Hunter be adapted to factor-in paired IRRs to give a better prediction of expansion size? PCR based assays will also be essential for confirmation and sizing of any repeats detected, not currently available diagnostically to our knowledge.

Created: 27 Oct 2023, 11:29 a.m. | Last Modified: 27 Oct 2023, 11:29 a.m.

Panel Version: 4.26

Comment on list classification: Promoting to amber but there is sufficient evidence to promote to green following GMS review, and configuration in the Rare Disease analysis pipeline. GMS expert review is required to confirm that the normal and pathogenic thresholds set are appropriate.

Created: 1 Mar 2023, 10:43 p.m. | Last Modified: 12 Jun 2023, 10:19 p.m.

Panel Version: 4.12

The FGF14 gene is associated with Spinocerebellar ataxia 27A (#193003) (SNVs) and Spinocerebellar ataxia 27B, late-onset (#620174) (repeat expansion) in OMIM.

PMID: 36516086 - Pellerin et al 2023 - in 6 French Canadian patients with autosomal dominant late-onset cerebellar ataxia (LOCA), from 3 families (2 from each family) were analysed and a deep intronic GAA repeat expansion in FGF14 was identified, as well as in 15 affected relatives. 250 GAA repeats was the smallest expansion in any affected family member. They also determined FGF14_GAA repeat expansion size of 66 French Canadian, 228 German, 20 Australian, and 31 Indian index patients plus 408 persons without ataxia. There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (P<0.001) and in the German series, P<0.001) The high proportion of French Canadian patients carrying the FGF14 expansion may correspond to a founder effect in this population.

PMID: 36493768 - Rafehi et al 2023 - 4/95 (4.2%) of Australian individuals with adult-onset ataxia were identified to have repeat expansions (GAA)>300 in FGF14 and a further 9 individuals with (GAA)>250. No control subjects had (GAA)>300 and only 0.6% of control subjects had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further 6 had (GAA)>250. Again no control subjects had (GAA)>335 and 5.3% control subjects had (GAA)>250. They conclude that (GAA)>335 are disease causing and fully penetrant while (GAA)>250 is likely pathogenic with reduced penetrance.

Created: 1 Mar 2023, 10:35 p.m. | Last Modified: 1 Mar 2023, 10:35 p.m.

Panel Version: 3.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spinocerebellar ataxia 27B, late-onset, OMIM:620174

Publications

• 36516086
• 36493768

I don't know

New STR disease loci reported to account for significant number of dominant late onset ataxia cases. Not current standard of care therefore no diagnostic accredited PCR assays available currently in UK.
Sources: Literature

Created: 15 Feb 2023, 12:56 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Late-onset cerebellar ataxia; Episodic features; Nystagmus

Publications

• PMID: 36516086