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

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
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
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引用次数: 0

摘要

背景:1型神经纤维瘤病(NF1)是最常见的遗传性疾病之一。NF1是由肿瘤抑制基因NF1的显性功能丧失致病变异(pv)引起的,NF1编码神经纤维蛋白,神经纤维蛋白是大鼠肉瘤蛋白的负调节因子。NF1是一种常染色体显性遗传病,具有完全外显性,但表达高度可变。由于广泛的临床变异性、疾病的进行性和突变谱的极端多样性,基因型-表型相关性的鉴定具有挑战性。只有少数NF1点变异与NF1患者的特定表型相关。方法:我们调查了一个大的、表型良好的NF1队列。结果:我们报告了112例NF1患者特异性NF1点变异的基因型-表型相关性分析:p.Arg1809错义变异与轻度NF1相关(n=24),而更严重的表型与密码子844-848 (n=27)、p.Arg1276 (n=25)和p.Lys1423 (n=35)错义变异相关。我们描述了p.a g1204错义变异(n=11)与患者中未观察到神经纤维瘤的新相关性。功能研究对于得出这些变异的潜在亚形态或显性负面影响的结论至关重要。结论:目前的数据证实了NF1的几个基因型-表型相关性,这可能与NF1患者特异性NF1 pv的管理和监测有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
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.
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