TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.,Genetics in Medicine

当前位置： X-MOL 学术 › Genet. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-05-28 , DOI: 10.1038/s41436-020-0823-4
Barbara Ogórek ₁ , Lana Hamieh ₁ , Hanna M Hulshof ₂ , Kathryn Lasseter ₁ , Katarzyna Klonowska ₁ , Hugo Kuijf ₃ , Romina Moavero _{4,

5} , Christoph Hertzberg ₆ , Bernhard Weschke ₇ , Kate Riney ₈ , Martha Feucht ₉ , Theresa Scholl ₉ , Pavel Krsek ₁₀ , Rima Nabbout ₁₁ , Anna C Jansen ₁₂ , Barbora Benova ₁₀ , Eleonora Aronica _{13,

14} , Lieven Lagae ₁₅ , Paolo Curatolo ₄ , Julita Borkowska ₁₆ , Krzysztof Sadowski ₁₆ , Dorota Domańska-Pakieła ₁₆ , Stef Janson ₁₇ , Piotr Kozlowski ₁₈ , Malgorzata Urbanska ₁₆ , Jacek Jaworski ₁₉ , Sergiusz Jozwiak _{16,

20} , Floor E Jansen ₂ , Katarzyna Kotulska ₁₆ , , David J Kwiatkowski ₁

Affiliation

Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Child Neurology, Brain Center University Medical Center Utrecht, Utrecht, The Netherlands.
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Diagnose- und Behandlungszentrum für Kinder, Vivantes-Klinikum Neukölln, Berlin, Germany.
Department of Child Neurology, Charité University Medicine Berlin, Berlin, Germany.
Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia/School of Medicine, University of Queensland, St Lucia, Queensland, Australia.
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna; "Affiliated Partner of ERN EpiCARE", Vienna, Austria.
Motol University Hospital, Charles University, Prague, Czech Republic.
Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, University Paris Descartes, Imagine Institute, Paris, France.
Pediatric Neurology Unit, UZ Brussel, Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium.
Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede the Netherlands, Utrecht, The Netherlands.
Department of Development and Regeneration Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium.
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
GenomeScan, Leiden, The Netherlands.
Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
International Institute of Molecular and Cell Biology, Warsaw, Poland.
Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.

Purpose

To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations.

Methods

Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2.

Results

Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2.

Conclusion

TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

中文翻译：

TSC2 致病变异可预测 TSC 婴儿的严重临床表现：EPISTOP 研究的结果。

目的

对一组 94 名患有结节性硬化症 (TSC) 的婴儿进行TSC1和TSC2的综合基因分型，并与临床表现相关联。

方法

婴儿在 4 个月大时入组，并接受强化临床监测，包括脑电图 (EEG)、脑磁共振成像 (MRI) 和神经心理学评估。靶向大规模平行测序 (MPS)、基因组测序和多重连接依赖性探针扩增 (MLPA) 用于TSC1 / TSC2中的变异检测。

结果

TSC1或TSC2的致病性变异在94 名受试者中的 93 名 (99%) 中被鉴定，其中 23 名在TSC1中，70 名在TSC2中。九名（10%）受试者有镶嵌现象。在 2 岁时评估的 24 项临床特征中有 8 项在TSC1与TSC2变异体中的发生率显着降低，包括皮质结节、低黑色素斑、面部血管纤维瘤、肾囊肿、耐药性癫痫、发育迟缓、室管膜下巨细胞星形细胞瘤和中位癫痫发作- 自由生存。此外，定量脑 MRI 分析显示TSC1与TSC2的结节和室管膜下结节/巨细胞星形细胞瘤体积存在显着差异。