Mehdi Benkirane, Cecilia Marelli, Ariane Choumert, Cyril Goizet, Olivier Patat, Claire Ewenczyk, Mathieu Anheim, André Mégarbané, Lise Larrieu, Cyril Charlin, Fabienne Ory Magne, Annabelle Chaussenot, Mélanie Fradin, Claire Guissart, Morgane Pointaux, Mireille Cossée, Marie-Claire Vincent, Anne Bergougnoux, Clément Hersent, Corinne Bareil, Agathe Roubertie, Frédérique Fluchère, Mathilde Renaud, Laurent Kremer, Christine Tranchant, Shahram Attarian, Sylvie Odent, Vincent Laugel, Ulrike Walther-Louvier, Beatrice Desnous, Eric Bieth, Isabelle Husson, Jean Phillipe Azulay, François Rivier, Bérénice Doray, Alexandra Durr, Safa Aouinti, Nicolas Molinari, Michel Koenig
{"title":"在弗里德赖希共济失调中，重复中断的类型和位置作为疾病严重程度和扩展大小的决定因素。","authors":"Mehdi Benkirane, Cecilia Marelli, Ariane Choumert, Cyril Goizet, Olivier Patat, Claire Ewenczyk, Mathieu Anheim, André Mégarbané, Lise Larrieu, Cyril Charlin, Fabienne Ory Magne, Annabelle Chaussenot, Mélanie Fradin, Claire Guissart, Morgane Pointaux, Mireille Cossée, Marie-Claire Vincent, Anne Bergougnoux, Clément Hersent, Corinne Bareil, Agathe Roubertie, Frédérique Fluchère, Mathilde Renaud, Laurent Kremer, Christine Tranchant, Shahram Attarian, Sylvie Odent, Vincent Laugel, Ulrike Walther-Louvier, Beatrice Desnous, Eric Bieth, Isabelle Husson, Jean Phillipe Azulay, François Rivier, Bérénice Doray, Alexandra Durr, Safa Aouinti, Nicolas Molinari, Michel Koenig","doi":"10.1016/j.gim.2025.101588","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions, but their impact only recently investigated.</p><p><strong>Methods: </strong>164 FRDA patients with biallelic expansions, and 15 non-FRDA patients were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for FRDA patients.</p><p><strong>Results: </strong>Three groups of FRDA patients were identified by the simultaneous analysis of the precise distance (\"depth\") between the interruptions (mostly non-triplet) and the 3' end of the expansion (P < 0.001), the smaller expansion size (P < 0.001), and AAO (P < 0.001). Classical FRDA corresponds to absence of interruption or interruption depth <8 repeats, with AAO often < 15 years (AUC = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8-18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15-34 years (AUC = 1; 95% CI, 1-1); vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1) and AAO >34 years. Multiple (>5) triplet interruptions hamper further expansion.</p><p><strong>Conclusion: </strong>This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101588"},"PeriodicalIF":6.2000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.\",\"authors\":\"Mehdi Benkirane, Cecilia Marelli, Ariane Choumert, Cyril Goizet, Olivier Patat, Claire Ewenczyk, Mathieu Anheim, André Mégarbané, Lise Larrieu, Cyril Charlin, Fabienne Ory Magne, Annabelle Chaussenot, Mélanie Fradin, Claire Guissart, Morgane Pointaux, Mireille Cossée, Marie-Claire Vincent, Anne Bergougnoux, Clément Hersent, Corinne Bareil, Agathe Roubertie, Frédérique Fluchère, Mathilde Renaud, Laurent Kremer, Christine Tranchant, Shahram Attarian, Sylvie Odent, Vincent Laugel, Ulrike Walther-Louvier, Beatrice Desnous, Eric Bieth, Isabelle Husson, Jean Phillipe Azulay, François Rivier, Bérénice Doray, Alexandra Durr, Safa Aouinti, Nicolas Molinari, Michel Koenig\",\"doi\":\"10.1016/j.gim.2025.101588\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions, but their impact only recently investigated.</p><p><strong>Methods: </strong>164 FRDA patients with biallelic expansions, and 15 non-FRDA patients were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for FRDA patients.</p><p><strong>Results: </strong>Three groups of FRDA patients were identified by the simultaneous analysis of the precise distance (\\\"depth\\\") between the interruptions (mostly non-triplet) and the 3' end of the expansion (P < 0.001), the smaller expansion size (P < 0.001), and AAO (P < 0.001). Classical FRDA corresponds to absence of interruption or interruption depth <8 repeats, with AAO often < 15 years (AUC = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8-18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15-34 years (AUC = 1; 95% CI, 1-1); vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1) and AAO >34 years. Multiple (>5) triplet interruptions hamper further expansion.</p><p><strong>Conclusion: </strong>This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.</p>\",\"PeriodicalId\":12717,\"journal\":{\"name\":\"Genetics in Medicine\",\"volume\":\" \",\"pages\":\"101588\"},\"PeriodicalIF\":6.2000,\"publicationDate\":\"2025-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genetics in Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.gim.2025.101588\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genetics in Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.gim.2025.101588","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.
Purpose: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions, but their impact only recently investigated.
Methods: 164 FRDA patients with biallelic expansions, and 15 non-FRDA patients were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for FRDA patients.
Results: Three groups of FRDA patients were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly non-triplet) and the 3' end of the expansion (P < 0.001), the smaller expansion size (P < 0.001), and AAO (P < 0.001). Classical FRDA corresponds to absence of interruption or interruption depth <8 repeats, with AAO often < 15 years (AUC = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8-18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15-34 years (AUC = 1; 95% CI, 1-1); vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1) and AAO >34 years. Multiple (>5) triplet interruptions hamper further expansion.
Conclusion: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.
期刊介绍：
Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health.
GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
