Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2 |
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Authors: | Angela Peron Aglaia Vignoli Francesca La Briola Emanuela Morenghi Lucia Tansini Rosa Maria Alfano Gaetano Bulfamante Silvia Terraneo Filippo Ghelma Giuseppe Banderali David H. Viskochil John C. Carey Maria Paola Canevini |
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Affiliation: | 1. Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy;2. Department of Health Sciences, Università degli Studi di Milano, Milan, Italy;3. Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA;4. Biostatistics Unit, Humanitas Clinical and Research Center, Milan, Italy;5. Department of Biomedical Sciences, Humanitas University, Milan, Italy;6. Human Pathology and Molecular Pathology Unit, San Paolo Hospital, Milan, Italy;7. Respiratory Unit, San Paolo Hospital, Milan, Italy;8. DAMA (Disabled Advanced Medical Assistance), San Paolo Hospital, Milan, Italy;9. Pediatrics Unit, San Paolo Hospital, Milan, Italy |
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Abstract: | Tuberous Sclerosis Complex (TSC) is a multisystemic condition caused by mutations in TSC1 or TSC2, but a pathogenic variant is not identified in up to 10% of the patients. The aim of this study was to delineate the phenotype of pediatric and adult patients with a definite clinical diagnosis of TSC and no mutation identified in TSC1 or TSC2.We collected molecular and clinical data of 240 patients with TSC, assessing over 50 variables. We compared the phenotype of the homogeneous group of individuals with No Mutation Identified (NMI) with that of TSC patients with a TSC1 and TSC2 pathogenic variant.9.17% of individuals were classified as NMI. They were diagnosed at an older age (p?=?0.001), had more frequent normal cognition (p 0.001) and less frequent epilepsy (p =?0.010), subependymal nodules (p?=?0.022) and giant cell astrocytomas (p?=?0.008) than patients with TSC2 pathogenic variants. NMI individuals showed more frequent bilateral and larger renal angiomyolipomas (p?=?0.001; p?=?0.003) and pulmonary involvement (trend) than patients with TSC1 pathogenic variants. Only one NMI individual had intellectual disability. None presented with a subependymal giant cell astrocytoma. Other medical problems not typical of TSC were found in 42.86%, without a recurrent pattern of abnormalities. Other TSC-associated neuropsychiatric disorders and drug-resistance in epilepsy were equally frequent in the three groups.This study provides a systematic clinical characterization of patients with TSC and facilitates the delineation of a distinctive phenotype indicative of NMI patients, with important implications for surveillance. |
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Keywords: | Deep phenotyping Genotype-phenotype correlation No mutation identified (NMI) Tuberous sclerosis complex (TSC) on behalf of the |
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