Laurence Pacot, Marinus Blok, Dominique Vidaud, Laura Fertitta, Ingrid Laurendeau, Audrey Coustier, Theodora Maillard, Cécile Barbance, Djihad Hadjadj, Manuela Ye, Dominique Lallemand, Salah Ferkal, Benoit Funalot, Ariane Lunati-Rozie, Bérénice Hebrard, Rakia Bhouri, Liesbeth Spruijt, Didier Bessis, David Geneviève, Vivian Vernimmen, Martinus P G Broen, Sabine Sigaudy, Sylvie Odent, Léna Damaj, Chloé Quélin, Laurent Pasquier, Valérie Layet, Brigitte Gilbert-Dussardier, Gaël Nicolas, Anne-Marie Guerrot, Bruno Leheup, Anne-Claire Bursztejn, Florence Petit, Odile Boute-Bénéjean, Yline Capri, Anne Guimier, Stanislas Lyonnet, Genevieve Baujat, Emmanuelle Bourrat, Bertrand Isidor, Mathilde Nizon, Sébastien Barbarot, Annick Toutain, Sophie Blesson, Julien Van-Gils, Fanny Morice-Picard, Séverine Audebert-Bellanger, Juliette Mazereeuw-Hautier, Alban Ziegler, Yves Alembik, Juliette Piard, Elise Brischoux-Boucher, Léa Guerrini-Rousseau, Julia Morera, Véronique Paquis-Flucklinger, Bruno Delobel, Jean-Luc Alessandri, Béatrice Parfait, Pierre Wolkenstein, Eric Pasmant
{"title":"神经纤维瘤病1型患者NF1点变异的精细基因型-表型相关性","authors":"Laurence Pacot, Marinus Blok, Dominique Vidaud, Laura Fertitta, Ingrid Laurendeau, Audrey Coustier, Theodora Maillard, Cécile Barbance, Djihad Hadjadj, Manuela Ye, Dominique Lallemand, Salah Ferkal, Benoit Funalot, Ariane Lunati-Rozie, Bérénice Hebrard, Rakia Bhouri, Liesbeth Spruijt, Didier Bessis, David Geneviève, Vivian Vernimmen, Martinus P G Broen, Sabine Sigaudy, Sylvie Odent, Léna Damaj, Chloé Quélin, Laurent Pasquier, Valérie Layet, Brigitte Gilbert-Dussardier, Gaël Nicolas, Anne-Marie Guerrot, Bruno Leheup, Anne-Claire Bursztejn, Florence Petit, Odile Boute-Bénéjean, Yline Capri, Anne Guimier, Stanislas Lyonnet, Genevieve Baujat, Emmanuelle Bourrat, Bertrand Isidor, Mathilde Nizon, Sébastien Barbarot, Annick Toutain, Sophie Blesson, Julien Van-Gils, Fanny Morice-Picard, Séverine Audebert-Bellanger, Juliette Mazereeuw-Hautier, Alban Ziegler, Yves Alembik, Juliette Piard, Elise Brischoux-Boucher, Léa Guerrini-Rousseau, Julia Morera, Véronique Paquis-Flucklinger, Bruno Delobel, Jean-Luc Alessandri, Béatrice Parfait, Pierre Wolkenstein, Eric Pasmant","doi":"10.1136/jmg-2025-110783","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene <i>NF1</i>, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few <i>NF1</i> point variants have been associated with a specific phenotype in NF1 patients.</p><p><strong>Methods: </strong>We investigated a large, well-phenotyped NF1 cohort.</p><p><strong>Results: </strong>We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific <i>NF1</i> point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.</p><p><strong>Conclusion: </strong>The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific <i>NF1</i> PVs.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Refined genotype-phenotype correlations in neurofibromatosis type 1 patients with <i>NF1</i> point variants.\",\"authors\":\"Laurence Pacot, Marinus Blok, Dominique Vidaud, Laura Fertitta, Ingrid Laurendeau, Audrey Coustier, Theodora Maillard, Cécile Barbance, Djihad Hadjadj, Manuela Ye, Dominique Lallemand, Salah Ferkal, Benoit Funalot, Ariane Lunati-Rozie, Bérénice Hebrard, Rakia Bhouri, Liesbeth Spruijt, Didier Bessis, David Geneviève, Vivian Vernimmen, Martinus P G Broen, Sabine Sigaudy, Sylvie Odent, Léna Damaj, Chloé Quélin, Laurent Pasquier, Valérie Layet, Brigitte Gilbert-Dussardier, Gaël Nicolas, Anne-Marie Guerrot, Bruno Leheup, Anne-Claire Bursztejn, Florence Petit, Odile Boute-Bénéjean, Yline Capri, Anne Guimier, Stanislas Lyonnet, Genevieve Baujat, Emmanuelle Bourrat, Bertrand Isidor, Mathilde Nizon, Sébastien Barbarot, Annick Toutain, Sophie Blesson, Julien Van-Gils, Fanny Morice-Picard, Séverine Audebert-Bellanger, Juliette Mazereeuw-Hautier, Alban Ziegler, Yves Alembik, Juliette Piard, Elise Brischoux-Boucher, Léa Guerrini-Rousseau, Julia Morera, Véronique Paquis-Flucklinger, Bruno Delobel, Jean-Luc Alessandri, Béatrice Parfait, Pierre Wolkenstein, Eric Pasmant\",\"doi\":\"10.1136/jmg-2025-110783\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene <i>NF1</i>, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few <i>NF1</i> point variants have been associated with a specific phenotype in NF1 patients.</p><p><strong>Methods: </strong>We investigated a large, well-phenotyped NF1 cohort.</p><p><strong>Results: </strong>We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific <i>NF1</i> point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.</p><p><strong>Conclusion: </strong>The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific <i>NF1</i> PVs.</p>\",\"PeriodicalId\":16237,\"journal\":{\"name\":\"Journal of Medical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jmg-2025-110783\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2025-110783","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Refined genotype-phenotype correlations in neurofibromatosis type 1 patients with NF1 point variants.
Background: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.
Methods: We investigated a large, well-phenotyped NF1 cohort.
Results: We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.
Conclusion: The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.