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Abstract Details

Expansion of an Intronic FGF14 GAA Short Tandem Repeat in Late-Onset Cerebellar Ataxia
Movement Disorders
ES2 - Emerging Science 2 (5:42 PM-5:48 PM)
003

LOCAs have until recently largely resisted genetic diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis.

To report on a novel autosomal dominant intronic GAA repeat expansion in the first intron of the fibroblast growth factor 14  gene (FGF14) causing late-onset cerebellar ataxia (LOCA).

We performed whole-genome sequencing on six cases from three large French-Canadian families with unsolved autosomal dominant LOCA and identified a candidate GAA repeat expansion in the first intron of FGF14. We determined a pathogenic threshold of (GAA)250 following segregation study within the three families and tested for an association between the repeat expansion and disease in (1) 66 French-Canadian cases and 209 controls, and (2) 228 German cases and 199 controls. We also screened 20 Australian and 31 Indian cases for the repeat expansion.

We identified 128 cases carrying an FGF14 GAA repeat expansion. The repeat expansion was present in 61%, 18%, 15%, and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. We found a significant association between FGF14 (GAA)250 expansions and LOCA in the French-Canadian (OR=105.60, 95% CI=31.09-334.20; p<0.001) and the German (OR=8.76, 95% CI=3.45-20.84; p<0.001) series. Our data suggest that (GAA)250-300 expansions are incompletely penetrant while larger expansions are fully penetrant. Cases developed a progressive cerebellar syndrome at an average age of 59 years. The ataxia was episodic at onset in 46% of cases. Downbeat nystagmus was observed in 42% of patients. Cerebellar atrophy was found in 74% of cases on MRI. 

This novel dominantly inherited intronic GAA repeat expansion in FGF14 is a common cause of LOCA. Our study underscores the importance of identifying non-coding repeat expansions, because they likely account for some of the missing heritability in late-onset neurodegenerative disorders.

Authors/Disclosures
David Pellerin, MD
PRESENTER
Dr. Pellerin has nothing to disclose.
Matt Danzi (University of Miami) Matt Danzi has nothing to disclose.
Carlo Wilke, MD Dr. Wilke has nothing to disclose.
Mathilde Renaud Mathilde Renaud has nothing to disclose.
Sarah Fazal (University of Miami) Ms. Fazal has nothing to disclose.
Marie-Josee Dicaire No disclosure on file
Carolin Kirsten Scriba, Other (Harry Perkins Institute of Medical Research) Ms. Scriba has received research support from the University of Western Australia. Ms. Scriba has received research support from the Australasian Genomic Technologies Association (AGTA).
Catherine Ashton, MBBS (Catherine Ashton) Dr. Ashton has nothing to disclose.
David Genis, Sr., MD Dr. GENIS has nothing to disclose.
Laura Molina Porcel, MD,PhD (Hospital Clínic, Barcelona, Spain) Dr. Molina Porcel has nothing to disclose.
Sara Nagy, MD (Deparment of Neurology, University Hospital Basel) Dr. Nagy has nothing to disclose.
Atchayaram Nalini Atchayaram Nalini has nothing to disclose.
Kym Boycott The institution of Kym Boycott has received research support from Genome Canada. The institution of Kym Boycott has received research support from CIHR.
Antoine Duquette, MD (CHUM) Dr. Duquette has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Reata. The institution of Dr. Duquette has received research support from Actelion. The institution of Dr. Duquette has received research support from Ataxia Canada/FARA.
Henry Houlden Henry Houlden has nothing to disclose.
Gianina Ravenscroft, PhD (Harry Perkins Institute and UWA) Dr. Ravenscroft has nothing to disclose.
Nigel G. Laing (University of Western Australia) Nigel G. Laing has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elslevier. The institution of Nigel G. Laing has received research support from Australian National Health and Medical Research Council. The institution of Nigel G. Laing has received research support from Australian Medical Research Future Fund. Nigel G. Laing has received publishing royalties from a publication relating to health care.
Phillipa Lamont, FRACP,PhD,MBBS (royal perth hospital) Prof. Lamont has nothing to disclose.
Ludger Schols, MD (Eberhard-Karls-University) Dr. Schols has received personal compensation in the range of $500-$4,999 for serving as a Consultant for VICO Therapeutics. Dr. Schols has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Schols has received research support from Vigil.
Roberta La Piana Roberta La Piana has nothing to disclose.
Matthis Synofzik (Hertie-Institute for Clinical Brain Research) Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Orphayzme Pharmaceuticals. The institution of Matthis Synofzik has received research support from EJPRD.
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine) Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
Bernard Brais, MD Dr. Brais has nothing to disclose.