Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis

Abstract

Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity.

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

“…The mutation detection rate of reported cohorts from other countries such as Greek. Russia and Brazil were 87%˜89% by using the same methods as ours or next generation sequencing [25][26][27]. While the earlier reports analyzed about 117 TSC children and 84 TSC patients from China presented the rate to 100% and 76%, respectively [15,28].…”

Morphologic, Immunohistochemical, and Genetic Differences Between High-grade and Low-grade Fetal Adenocarcinomas of the Lung

“…The de novo defects in TSC1 / 2 are considered as the main cause and a diagnostic molecular marker of tuberous sclerosis. 30 It has been hypothesized that TSC2 mutations abolish the ability of this protein to inhibit Wnt-stimulated β-catenin-dependent transcription, 31 , 32 suggesting that TSC2 and CTNNB1 mutations could be synergistic in activating the Wnt/β-catenin pathway in LG-FLAC. However, CTNNB1 mutations are relatively broad-spectrum across many cancer types, rendering the coexistence with less common mutations in DICER1 and MYCN more indicative and specific for LG-FLAC diagnosis.…”

“…In the current study, another TSC2 mutation (R1032*, 2.7%) was identified in one LG-FLAC sample (Table S1). The de novo defects in TSC1 / 2 are considered as the main cause and a diagnostic molecular marker of tuberous sclerosis 30. It has been hypothesized that TSC2 mutations abolish the ability of this protein to inhibit Wnt-stimulated β-catenin-dependent transcription,31,32 suggesting that TSC2 and CTNNB1 mutations could be synergistic in activating the Wnt/β-catenin pathway in LG-FLAC.…”

Whole Exome Sequencing in a Series of Patients with a Clinical Diagnosis of Tuberous Sclerosis Not Confirmed by Targeted TSC1/TSC2 Sequencing

“…However, they could not find any pathogenic variants in the above mentioned six genes. In 2018, a Russian study performed WES as a part of their experiments on five NMI patients, using Illumina Nextera Kit for exome enrichment and Illumina MiSeq, but they failed to identify disease-causing mutation candidate genes among their NMI patients [ 28 ].…”