Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. Pellerin, D., Danzi, M. C., Wilke, C., Renaud, M., Fazal, S., Dicaire, M., Scriba, C. K., Ashton, C., Yanick, C., Beijer, D., Rebelo, A., Rocca, C., Jaunmuktane, Z., Sonnen, J. A., Lariviere, R., Genis, D., Molina Porcel, L., Choquet, K., Sakalla, R., Provost, S., Robertson, R., Allard-Chamard, X., Tetreault, M., Reiling, S. J., Nagy, S., Nishadham, V., Purushottam, M., Vengalil, S., Bardhan, M., Nalini, A., Chen, Z., Mathieu, J., Massie, R., Chalk, C. H., Lafontaine, A., Evoy, F., Rioux, M., Ragoussis, J., Boycott, K. M., Dube, M., Duquette, A., Houlden, H., Ravenscroft, G., Laing, N. G., Lamont, P. J., Saporta, M. A., Schule, R., Schols, L., La Piana, R., Synofzik, M., Zuchner, S., & Brais, B. The New England journal of medicine, 388(2):128–141, January, 2023. Place: United Statesdoi abstract bibtex BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]\textgreater/=250). There was significant association between FGF14 (GAA)\textgreater/=250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P\textless0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P\textless0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)\textgreater/=250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
@article{pellerin_deep_2023,
title = {Deep {Intronic} {FGF14} {GAA} {Repeat} {Expansion} in {Late}-{Onset} {Cerebellar} {Ataxia}.},
volume = {388},
copyright = {Copyright (c) 2022 Massachusetts Medical Society.},
issn = {1533-4406 0028-4793},
doi = {10.1056/NEJMoa2207406},
abstract = {BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]{\textgreater}/=250). There was significant association between FGF14 (GAA){\textgreater}/=250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95\% confidence interval [CI], 31.09 to 334.20; P{\textless}0.001) and in the German series (odds ratio, 8.76; 95\% CI, 3.45 to 20.84; P{\textless}0.001). The repeat expansion was present in 61\%, 18\%, 15\%, and 10\% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA){\textgreater}/=250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).},
language = {eng},
number = {2},
journal = {The New England journal of medicine},
author = {Pellerin, David and Danzi, Matt C. and Wilke, Carlo and Renaud, Mathilde and Fazal, Sarah and Dicaire, Marie-Josee and Scriba, Carolin K. and Ashton, Catherine and Yanick, Christopher and Beijer, Danique and Rebelo, Adriana and Rocca, Clarissa and Jaunmuktane, Zane and Sonnen, Joshua A. and Lariviere, Roxanne and Genis, David and Molina Porcel, Laura and Choquet, Karine and Sakalla, Rawan and Provost, Sylvie and Robertson, Rebecca and Allard-Chamard, Xavier and Tetreault, Martine and Reiling, Sarah J. and Nagy, Sara and Nishadham, Vikas and Purushottam, Meera and Vengalil, Seena and Bardhan, Mainak and Nalini, Atchayaram and Chen, Zhongbo and Mathieu, Jean and Massie, Rami and Chalk, Colin H. and Lafontaine, Anne-Louise and Evoy, Francois and Rioux, Marie-France and Ragoussis, Jiannis and Boycott, Kym M. and Dube, Marie-Pierre and Duquette, Antoine and Houlden, Henry and Ravenscroft, Gianina and Laing, Nigel G. and Lamont, Phillipa J. and Saporta, Mario A. and Schule, Rebecca and Schols, Ludger and La Piana, Roberta and Synofzik, Matthis and Zuchner, Stephan and Brais, Bernard},
month = jan,
year = {2023},
pmid = {36516086},
pmcid = {PMC10042577},
note = {Place: United States},
keywords = {*Cerebellar Ataxia/genetics/pathology, *DNA Repeat Expansion/genetics, *Introns/genetics, Australia, Canada, Friedreich Ataxia/genetics/pathology, Humans},
pages = {128--141},
}
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{"_id":"2GbYtbKJAgzWXwZ7p","bibbaseid":"pellerin-danzi-wilke-renaud-fazal-dicaire-scriba-ashton-etal-deepintronicfgf14gaarepeatexpansioninlateonsetcerebellarataxia-2023","author_short":["Pellerin, D.","Danzi, M. C.","Wilke, C.","Renaud, M.","Fazal, S.","Dicaire, M.","Scriba, C. K.","Ashton, C.","Yanick, C.","Beijer, D.","Rebelo, A.","Rocca, C.","Jaunmuktane, Z.","Sonnen, J. A.","Lariviere, R.","Genis, D.","Molina Porcel, L.","Choquet, K.","Sakalla, R.","Provost, S.","Robertson, R.","Allard-Chamard, X.","Tetreault, M.","Reiling, S. J.","Nagy, S.","Nishadham, V.","Purushottam, M.","Vengalil, S.","Bardhan, M.","Nalini, A.","Chen, Z.","Mathieu, J.","Massie, R.","Chalk, C. H.","Lafontaine, A.","Evoy, F.","Rioux, M.","Ragoussis, J.","Boycott, K. M.","Dube, M.","Duquette, A.","Houlden, H.","Ravenscroft, G.","Laing, N. G.","Lamont, P. J.","Saporta, M. A.","Schule, R.","Schols, L.","La Piana, R.","Synofzik, M.","Zuchner, S.","Brais, B."],"bibdata":{"bibtype":"article","type":"article","title":"Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.","volume":"388","copyright":"Copyright (c) 2022 Massachusetts Medical Society.","issn":"1533-4406 0028-4793","doi":"10.1056/NEJMoa2207406","abstract":"BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]\\textgreater/=250). There was significant association between FGF14 (GAA)\\textgreater/=250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P\\textless0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P\\textless0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)\\textgreater/=250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).","language":"eng","number":"2","journal":"The New England journal of medicine","author":[{"propositions":[],"lastnames":["Pellerin"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Danzi"],"firstnames":["Matt","C."],"suffixes":[]},{"propositions":[],"lastnames":["Wilke"],"firstnames":["Carlo"],"suffixes":[]},{"propositions":[],"lastnames":["Renaud"],"firstnames":["Mathilde"],"suffixes":[]},{"propositions":[],"lastnames":["Fazal"],"firstnames":["Sarah"],"suffixes":[]},{"propositions":[],"lastnames":["Dicaire"],"firstnames":["Marie-Josee"],"suffixes":[]},{"propositions":[],"lastnames":["Scriba"],"firstnames":["Carolin","K."],"suffixes":[]},{"propositions":[],"lastnames":["Ashton"],"firstnames":["Catherine"],"suffixes":[]},{"propositions":[],"lastnames":["Yanick"],"firstnames":["Christopher"],"suffixes":[]},{"propositions":[],"lastnames":["Beijer"],"firstnames":["Danique"],"suffixes":[]},{"propositions":[],"lastnames":["Rebelo"],"firstnames":["Adriana"],"suffixes":[]},{"propositions":[],"lastnames":["Rocca"],"firstnames":["Clarissa"],"suffixes":[]},{"propositions":[],"lastnames":["Jaunmuktane"],"firstnames":["Zane"],"suffixes":[]},{"propositions":[],"lastnames":["Sonnen"],"firstnames":["Joshua","A."],"suffixes":[]},{"propositions":[],"lastnames":["Lariviere"],"firstnames":["Roxanne"],"suffixes":[]},{"propositions":[],"lastnames":["Genis"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Molina","Porcel"],"firstnames":["Laura"],"suffixes":[]},{"propositions":[],"lastnames":["Choquet"],"firstnames":["Karine"],"suffixes":[]},{"propositions":[],"lastnames":["Sakalla"],"firstnames":["Rawan"],"suffixes":[]},{"propositions":[],"lastnames":["Provost"],"firstnames":["Sylvie"],"suffixes":[]},{"propositions":[],"lastnames":["Robertson"],"firstnames":["Rebecca"],"suffixes":[]},{"propositions":[],"lastnames":["Allard-Chamard"],"firstnames":["Xavier"],"suffixes":[]},{"propositions":[],"lastnames":["Tetreault"],"firstnames":["Martine"],"suffixes":[]},{"propositions":[],"lastnames":["Reiling"],"firstnames":["Sarah","J."],"suffixes":[]},{"propositions":[],"lastnames":["Nagy"],"firstnames":["Sara"],"suffixes":[]},{"propositions":[],"lastnames":["Nishadham"],"firstnames":["Vikas"],"suffixes":[]},{"propositions":[],"lastnames":["Purushottam"],"firstnames":["Meera"],"suffixes":[]},{"propositions":[],"lastnames":["Vengalil"],"firstnames":["Seena"],"suffixes":[]},{"propositions":[],"lastnames":["Bardhan"],"firstnames":["Mainak"],"suffixes":[]},{"propositions":[],"lastnames":["Nalini"],"firstnames":["Atchayaram"],"suffixes":[]},{"propositions":[],"lastnames":["Chen"],"firstnames":["Zhongbo"],"suffixes":[]},{"propositions":[],"lastnames":["Mathieu"],"firstnames":["Jean"],"suffixes":[]},{"propositions":[],"lastnames":["Massie"],"firstnames":["Rami"],"suffixes":[]},{"propositions":[],"lastnames":["Chalk"],"firstnames":["Colin","H."],"suffixes":[]},{"propositions":[],"lastnames":["Lafontaine"],"firstnames":["Anne-Louise"],"suffixes":[]},{"propositions":[],"lastnames":["Evoy"],"firstnames":["Francois"],"suffixes":[]},{"propositions":[],"lastnames":["Rioux"],"firstnames":["Marie-France"],"suffixes":[]},{"propositions":[],"lastnames":["Ragoussis"],"firstnames":["Jiannis"],"suffixes":[]},{"propositions":[],"lastnames":["Boycott"],"firstnames":["Kym","M."],"suffixes":[]},{"propositions":[],"lastnames":["Dube"],"firstnames":["Marie-Pierre"],"suffixes":[]},{"propositions":[],"lastnames":["Duquette"],"firstnames":["Antoine"],"suffixes":[]},{"propositions":[],"lastnames":["Houlden"],"firstnames":["Henry"],"suffixes":[]},{"propositions":[],"lastnames":["Ravenscroft"],"firstnames":["Gianina"],"suffixes":[]},{"propositions":[],"lastnames":["Laing"],"firstnames":["Nigel","G."],"suffixes":[]},{"propositions":[],"lastnames":["Lamont"],"firstnames":["Phillipa","J."],"suffixes":[]},{"propositions":[],"lastnames":["Saporta"],"firstnames":["Mario","A."],"suffixes":[]},{"propositions":[],"lastnames":["Schule"],"firstnames":["Rebecca"],"suffixes":[]},{"propositions":[],"lastnames":["Schols"],"firstnames":["Ludger"],"suffixes":[]},{"propositions":[],"lastnames":["La","Piana"],"firstnames":["Roberta"],"suffixes":[]},{"propositions":[],"lastnames":["Synofzik"],"firstnames":["Matthis"],"suffixes":[]},{"propositions":[],"lastnames":["Zuchner"],"firstnames":["Stephan"],"suffixes":[]},{"propositions":[],"lastnames":["Brais"],"firstnames":["Bernard"],"suffixes":[]}],"month":"January","year":"2023","pmid":"36516086","pmcid":"PMC10042577","note":"Place: United States","keywords":"*Cerebellar Ataxia/genetics/pathology, *DNA Repeat Expansion/genetics, *Introns/genetics, Australia, Canada, Friedreich Ataxia/genetics/pathology, Humans","pages":"128–141","bibtex":"@article{pellerin_deep_2023,\n\ttitle = {Deep {Intronic} {FGF14} {GAA} {Repeat} {Expansion} in {Late}-{Onset} {Cerebellar} {Ataxia}.},\n\tvolume = {388},\n\tcopyright = {Copyright (c) 2022 Massachusetts Medical Society.},\n\tissn = {1533-4406 0028-4793},\n\tdoi = {10.1056/NEJMoa2207406},\n\tabstract = {BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]{\\textgreater}/=250). There was significant association between FGF14 (GAA){\\textgreater}/=250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95\\% confidence interval [CI], 31.09 to 334.20; P{\\textless}0.001) and in the German series (odds ratio, 8.76; 95\\% CI, 3.45 to 20.84; P{\\textless}0.001). The repeat expansion was present in 61\\%, 18\\%, 15\\%, and 10\\% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA){\\textgreater}/=250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).},\n\tlanguage = {eng},\n\tnumber = {2},\n\tjournal = {The New England journal of medicine},\n\tauthor = {Pellerin, David and Danzi, Matt C. and Wilke, Carlo and Renaud, Mathilde and Fazal, Sarah and Dicaire, Marie-Josee and Scriba, Carolin K. and Ashton, Catherine and Yanick, Christopher and Beijer, Danique and Rebelo, Adriana and Rocca, Clarissa and Jaunmuktane, Zane and Sonnen, Joshua A. and Lariviere, Roxanne and Genis, David and Molina Porcel, Laura and Choquet, Karine and Sakalla, Rawan and Provost, Sylvie and Robertson, Rebecca and Allard-Chamard, Xavier and Tetreault, Martine and Reiling, Sarah J. and Nagy, Sara and Nishadham, Vikas and Purushottam, Meera and Vengalil, Seena and Bardhan, Mainak and Nalini, Atchayaram and Chen, Zhongbo and Mathieu, Jean and Massie, Rami and Chalk, Colin H. and Lafontaine, Anne-Louise and Evoy, Francois and Rioux, Marie-France and Ragoussis, Jiannis and Boycott, Kym M. and Dube, Marie-Pierre and Duquette, Antoine and Houlden, Henry and Ravenscroft, Gianina and Laing, Nigel G. and Lamont, Phillipa J. and Saporta, Mario A. and Schule, Rebecca and Schols, Ludger and La Piana, Roberta and Synofzik, Matthis and Zuchner, Stephan and Brais, Bernard},\n\tmonth = jan,\n\tyear = {2023},\n\tpmid = {36516086},\n\tpmcid = {PMC10042577},\n\tnote = {Place: United States},\n\tkeywords = {*Cerebellar Ataxia/genetics/pathology, *DNA Repeat Expansion/genetics, *Introns/genetics, Australia, Canada, Friedreich Ataxia/genetics/pathology, Humans},\n\tpages = {128--141},\n}\n\n","author_short":["Pellerin, D.","Danzi, M. 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