Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA.
Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA.
Am J Med Genet A. 2024 Jun;194(6):e63569. doi: 10.1002/ajmg.a.63569. Epub 2024 Feb 17.
Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome-wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes.
在一般人群中发现的常见遗传变异已被证明会增加某些遗传疾病个体的表型风险。高达 90%的结节性硬化症 (TSC) 患者受到某种类型的癫痫的影响，但在 TSC 相关癫痫的背景下，尚未评估导致普通人群癫痫风险的常见变异。了解这一点对于帮助揭示 TSC 中癫痫的潜在发病机制非常重要，因为目前对此仍不完全了解，而且在该人群中，不受控制的癫痫是一个主要问题。为了评估癫痫的常见遗传修饰因子，我们的研究汇集了 369 名 TSC 患者的表型和基因型数据，以评估已知和新的癫痫常见变异。我们没有发现证据表明在一般人群中最大的癫痫全基因组关联研究中发现的已知癫痫变异具有增强的遗传外显率，但在 TSC 背景下支持新的常见癫痫变异。具体来说，我们在 SLC7A1 中发现了一个新的信号，该信号可能在与 TSC 和癫痫相关的途径中具有功能作用。我们的研究强调需要进一步评估 TSC 中的遗传修饰因子，以帮助进一步了解 TSC 中的癫痫，并改善结果。
