Repeat deep intronic FGF14 expansion associated with late-onset cerebral ataxia

1. The frequency of dominant deep GAA expansion in FGF14 The gene has been found among French Canadian patients with late-onset cerebellar ataxia (LOCA).

2. This candidate pathological marker was found to reduce expression FGF14 The gene product, fibroblast growth factor 14 (FGF14), in cerebral tissue and motor neurons.

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Study rundown: LOCAs are a diverse group of neurodegenerative diseases that present as a progressive ataxia syndrome with onset in late adulthood. LOCAs are rare and genetic testing to date has yielded high false-negative rates. This may be due to the inconsistent capabilities of standard genomic sequencing technologies in detecting some variations, such as tandem repeat expansions. The current study investigated the use of long-read nanopore sequencing and specialized software to detect recurrent expansions in FGF4 The gene among six French Canadian LOCA patients. A pathological threshold of 250 or more GAA sequence repeats was found deep in the first intron. This candidate gene marker was found to be associated with an increased risk of LOCA in a subsequent case-control study in French Canadian and German patients. Furthermore, postmortem examinations of cerebellar tissue and motor neurons derived from induced pluripotent stem cells (iPSC) revealed decreased transcription and expression of FGF14. The study showed that the expansion of GAA repeats the expansion in the first intron of FGF14 It was related to LOCA and highlighted the importance of examining non-coding regions when investigating neurodegenerative diseases.

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in depth [case-control study]: This multi-design, multi-stage study was an discovery genetic analysis of confirmed French-Canadian LOCA patients. A combination of case-control association studies, and a subsequent in vitro functional assay to examine the association of GAA intronic repeat expansion in the FGF14 gene with LOCA. Patients who had progressive ataxia with onset at or after age 30 years, without features of multisystem atrophy, acquired disease, or positive results on genetic screening for known ataxia disorders were eligible for inclusion. Six French Canadian patients with LOCA were studied in the discovery phase. The FGF14 repeat locus was found as a candidate marker when the genomes of these patients were compared with a control group. This region was then amplified using polymerase chain reaction and sequenced by long-read nanopore technology. An extension of the GAA repeat deep into the first intron of FGF14 was identified as the pathogenic variant, with a threshold of at least 250 repeats ([GAA]≥ 250). Next, two association studies were conducted between a group of French Canadians (66 patients and 209 controls) and a German (228 patients and 199 controls). The FGF14 [GAA]An expansion of ≥250 was associated with the strength of LOCA. The odds ratio was 105.60 in the French Canadian group (95% confidence interval [CI], 31.09 to 334.20; p < 0.001) and 8.76 in the German group (95% CI, 3.45 to 20.84; p < 0.001). In addition, the FGF14 [GAA]Expansion ≥250 was found in 61%, 18%, 15%, and 10% of the French-Canadian, German, Australian, and Indian cohorts of index patients, respectively. Finally, a functional analysis was performed in postmortem tissues from iPSC lines established from European LOCA patients and controls. In both assays, the FGF14 [GAA]Expansion ≥250 has been shown to result in lower expression of both FGF14 RNA and its gene product, FGF14 when compared to non-pathological controls. Overall, these results showed that expansion of a dominant GAA repeat in the intron of FGF14 was associated with LOCA.

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