Original from: Genomeweb
New research suggests that a subset of late-onset cerebellar ataxia cases may be caused by repeat expansions involving the fibroblast growth factor 14-coding gene FGF14.
As they reported in the New England Journal of Medicine on Wednesday, researchers at McGillUniversity, the University of Miami's Miller School of Medicine, and elsewhere started with whole-genome sequencing on half a dozen LOCA patients from three affected French Canadian families. The researchers used ExpansionHunter Denovo software and targeted nanopore long-read sequencing to narrow in on an FGF14 repeat expansion with potential ties to the neurodegenerative conditions.
"We used bioinformatics tools and long-read sequencing to search for novel pathogenic repeat expansions in patients with [late-onset cerebellar ataxia]," the authors wrote.
After confirming the repeat expansions, the team turned to repeat-primed PCR, targeted long-read nanopore sequencing, or PCR amplification with gel electrophoresis to search for the FGF14 repeat expansion in additional cases, including another 66 French Canadian late-onset cerebellar ataxia cases and 209 unaffected controls from Quebec; 228 cases and 199 controls from Germany; and dozens more cases from Australia and India.
The GAA repeat expansion, which was found in FGF14's first intron, turned up in 61 percent of the French Canadian late-onset cerebellar ataxia cases considered, the team reported. In contrast, the repeat was rare in French Canadians without late-onset cerebellar ataxia, appearing in only three of the 209 control individuals.
The researchers detected the repeat expansion in late-onset cerebellar ataxia patients from other populations, albeit in a smaller proportion of cases. They saw the FGF14 repeat expansion in 18 percent of the German cases and 15 percent of the Australian cases, but just 10 percent of late-onset cerebellar ataxia cases from India.
"The high proportion of French Canadian patients carrying the FGF14 expansion may correspond to a founder effect in this population, in which such effects are known to be common," the researchers wrote, noting that several French Canadian patients appeared to share a related haplotype.
After additional testing in family members of index cases, the researchers tracked down the repeat expansion in 128 late-onset cerebellar ataxia-affected individuals.
Through experiments on post-mortem brain samples from two French Canadian individuals with late-onset cerebellar ataxia, the investigators characterized parts of the brain with more or less pronounced atrophy. Meanwhile, their expression experiments pointed to lower-than-usual FGF14 levels in post-mortem brain samples from two late-onset cerebellar ataxia patients carrying the repeat expansion and in induced pluripotent stem cell-derived motor neurons from affected individuals.
The team's clinical analyses suggested that repeat expansions are longer and more frequently transmitted in female parents than in male parents. Repeat expansion sizes also seemed to coincide somewhat with certain clinical features such as age of onset for late-onset cerebellar ataxia patients.
The available clinical data suggested that a treatment known as acetazolamide led to clinical improvements for nine of 23 patients receiving it, the researchers reported. On the other hand, a drug called 4-aminopyridine appeared to curb ataxia symptom severity and regularity in seven of eight patients.
"This opens the door to a clinical trial of this [aminopyridine] drug in these patients," senior and corresponding author Bernard Brais, a neurologist and researcher at McGill University's Montreal Neurological Hospital and Institute, said in a statement, adding that the work "makes genetic testing possible so people and families can arrive at the end of their long diagnostic journey."
Source: Late-Onset Ataxia Linked to New Repeat Expansion in FGF14 Gene
China Association of In-vitro Diagnostics
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