Novel TSC1 and TSC2 gene mutations in Chinese patients with tuberous sclerosis complex

Yu, Tingting; He, Yingzhong; Niu, Li; Zhou, Ye; Wang, Zhiping; Fu, Qin; Wang, Jiwen; Wang, Jian

doi:10.1016/j.clineuro.2017.01.015

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…Most of these patients showed seizures and intellectual disability (N = 20/21; 95%) regardless of whether they harbored a PV in TSC1 or TSC2; however, this feature could be biased because the study population was drawn from a tertiary referral hospital, where most of the cases show a severe condition. We found that cardiac rhabdomyomas and renal angiomyolipomas were more common in patients with a PV in TSC2 than in TSC1 (7:1 and 4:1, respectively); in this, our results are similar to those of other published studies 26,34,42 . Even though cardiac rhabdomyomas are the most common prenatal cardiac tumor related to TSC (50-86% of cases), the absence of other manifestations at this age makes it difficult to establish a definitive diagnosis 46 .…”

Section: Discussionsupporting

confidence: 91%

“…This is expected since this disease presents high allelic and locus heterogeneity, and emphasizes the importance of implementing multiple and diverse molecular techniques to evaluate coding and non-coding regions in both genes, and to discriminate SV from CNV. Our results are similar to those of Yu et al 42 , who found a high percentage (54%) of new TSC variants but included a very limited number of cases (N = 11).…”

Section: Discussionsupporting

confidence: 91%

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First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Reyna-Fabián

Hernández‐Martínez

Alcántara-Ortigoza

et al. 2020

Sci Rep

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echavarría 4 , carlos G. todd-Quiñones 5,6 & Ariadna González-del Angel 1* the aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (tSc) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (pV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the pV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism. Tuberous sclerosis complex (TSC; MIM #191100, MIM #613254) is an autosomal dominant syndrome characterized by the presence of multiple hamartomas in different organs and systems. The incidence is about 0.1-1/10,000 births and the prevalence varies from 1/6,000 to 1/10,000 among different populations 1-3. The manifestations of TSC are highly variable among individuals and even within the same family 4 , but the most common clinical features are localized in skin and central nervous system 5-7. TSC is caused by pathogenic variants (PV) in the tumor suppressor-genes, TSC1 (tuberous sclerosis complex 1, MIM *605284, 9q34.13) and TSC2 (tuberous sclerosis complex 2, MIM *191092, 16p13.3). These PV can be detected by various molecular techniques, such as single-strand conformational polymorphism (SSCP), direct Sanger sequencing (SS), multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS). There are currently more than 2,000 pathogenic TSC1/TSC2 variants described in the Leiden Open Variation Database (www.lovd.nl/TSC1 and www.lovd.nl/TSC2) 8 ; of them, 21-26% are located in TSC1 and 69-79% in TSC2 9,10. In approximately 5-25% of the analyzed TSC cases, a PV could not be identified in either gene 9,11,12. The emergence of new techniques, such as NGS, has significantly increased the mutation detection rate

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Reyna-Fabián

Hernández‐Martínez

Alcántara-Ortigoza

et al. 2020

Sci Rep

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“…Though no obvious mutation hot spots were observed, mutations were identified more often in exon 8, 15 of TSC1 gene and exon 34, 36, 40 and 41 of TSC2 gene (GAP-related and Rabaptin binding domains) among the cohorts in China (Fig. 3B & C) [30][31][32][33][34]. Nevertheless, using both direct sequencing and MLPA, there were still left with a set of 14 (18.2%) patients in whom no mutation was identified.…”

Section: Discussionmentioning

confidence: 98%

Tuberous Sclerosis Complex in Chinese patients: Phenotypic analysis and mutational screening of TSC1/TSC2 genes

Lin

Zeng

Zhao

et al. 2019

Seizure

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Tuberous sclerosis complex (TSC) is characterized by the development of hamartomas in multiple organ systems. This study attempted to screen mutations and to investigate the mutation distribution and related phenotypes including epilepsy of Chinese TSC patients. Methods: We performed the genotypic analysis of TSC1 and TSC2 genes in 77 unrelated Chinese TSC patients using direct Sanger sequencing and Multiplex ligation-dependent probe amplification (MLPA). Results: Mutations were identified in a total of 63 (81.8%) cases, including 18 TSC1 mutations (8 nonsense mutations, 6 frameshift, 1 in-frame shift, 1 missense and 2 splice-site) and 45 TSC2 mutations (13 missense, 3 nonsense, 6 splicing, 6 in-frame shift,12 frameshift mutations and 5 large deletions). Large deletions were presented exclusively in TSC2 gene, accounting for 7.9% of all mutations in this study. Fourteen novel mutations were identified in this study. Conclusions: Epilepsy occurs in approximately 75.3% (58/77) of patients. Hypomelanotic macules occurred significantly more often in patients with TSC2 mutations and cases with TSC1/TSC2 mutations had a significantly higher frequency of cortical nodule than patients with no mutations identified. Overall, our data expands the spectrum of mutations associated with the TSC loci and will be of value to the genetic counseling in patients with the disease.

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“…In general, two-thirds of TSC cases are sporadic. [4] The present case was familial, given that the patient's mother carried the same mutation as her daughter.…”

Section: Discussionmentioning

confidence: 92%

“…This type of neurocutaneous syndrome is caused by mutations in the TSC1 or TSC2 gene, and over 300 and 900 mutations, respectively, in the genes been recorded in the Human Gene Mutation Database. [4] TSC2 mutations are 3 times more common than TSC1 mutations in tumor suppressor genes and associated with more severe neurodevelopment impairment. [5] The cause for TSC in patients without TSC1 / TSC2 mutation remains unknown and may be related to either a third gene and/or regulatory DNA controlling TSC1 or TSC2 .…”

Section: Discussionmentioning

confidence: 99%

Tuberous sclerosis complex presenting as convulsive status epilepticus followed by hypoxic cerebropathy

Liu¹,

Zhang

Hao

et al. 2019

Medicine

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Rationale: Tuberous sclerosis complex (TSC) is a relatively rare, autosomal dominant, and progressive neurocutaneous disorder involving multiple organs. Heterozygous mutations in the TSC1 gene located on chromosome 9 (9q34.13) or the TSC2 gene located on chromosome 16 (16p13.3) have been shown to be responsible for this disorder. The most common clinical manifestations are abnormalities of the skin, brain, kidney, heart, and lungs. Although all seizure types have been observed in TSC patients, the present case is the first in the literature to present with convulsive status epilepticus followed by hypoxic cerebropathy. Patient concerns: A 33-month-old girl presented with fever and seizure followed by unconsciousness for 6 hours. Physical examination showed 4 hypopigmented macules with diameters exceeding 5 mm. Initial magnetic resonance imaging of the brain revealed diffuse edema in the bilateral cerebral cortex, cortical tubers, and subependymal nodules. Video electroencephalography showed no epileptiform activity, but diffuse slow waves intermixed with small fast waves were seen for all leads. Computed tomography brain scanning revealed bilateral cortex edema and calcified subependymal nodules. Diagnosis: Combined with her clinical presentation, the patient was diagnosed with TSC after molecular analysis revealed she had inherited the TSC2 c.1832G>A (p.R611Q) mutation from her mother. Interventions: The patient received anti-infection therapy, mannitol dehydration, hyperbaric oxygen treatment, and topiramate. Outcomes: One month later, the patient was in a decorticate state, presenting with unconsciousness and bilateral arm flexion and leg extension. At 6 weeks, repeated electroencephalography was normal. Lessons: In addition to the present case report, rare studies have reported cases of TSC presenting as convulsive status epileticus followed by hypoxic cerebropathy, which may be strongly associated with a poor prognosis. Patients with the characteristic skin lesions and epilepsy should be carefully evaluated for the possible diagnosis of TSC.

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Novel TSC1 and TSC2 gene mutations in Chinese patients with tuberous sclerosis complex

Cited by 7 publications

References 26 publications

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Tuberous Sclerosis Complex in Chinese patients: Phenotypic analysis and mutational screening of TSC1/TSC2 genes

Tuberous sclerosis complex presenting as convulsive status epilepticus followed by hypoxic cerebropathy

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