Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.
Department of Clinical Genetics, Erasmus Medical Center, 3015 Rotterdam, The Netherlands.
Genes (Basel). 2024 Nov 3;15(11):1432. doi: 10.3390/genes15111432.
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the and tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. and encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of and variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to and in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in and 88 (83%) in . Of these, 35 were novel. Disruption of TSC1/2 activity was demonstrated for seven variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis.
结节性硬化症复合征（TSC）是一种常染色体显性遗传的神经发育障碍和多系统疾病，由 和 肿瘤抑制基因中的致病 DNA 改变引起。TSC 的分子遗传学诊断可确认临床诊断，有助于实施适当的护理和监测。 和 编码 TSC1/2 复合物（TSC1/2）的核心组成部分，是机械靶标雷帕霉素（MTOR）复合物 1（TORC1）的负调节剂。对 和 变体对 TORC1 活性的影响的功能分析有助于确定变体的致病性。我们在 116 名具有明确 TSC 临床诊断的个体的 DNA 中搜索了 和 的致病改变。对错义变体和框内缺失进行了功能评估。在 106 例（91%）中鉴定出致病性 DNA 改变；在 中 18 例（17%），在 中 88 例（83%）。其中 35 例为新发现。七种 变体的 TSC1/2 活性被破坏。分子诊断在很大比例的病例中确认了 TSC 的临床诊断。功能评估有助于确定变体的致病性，是 DNA 分析的有用补充。
