Clinical Genetic Service, Department of Health, Hong Kong Children's Hospital, 1 Shing Cheong Road, Kowloon Bay, Hong Kong SAR, China.
Clinical Genetic Service, Department of Health, Hong Kong Children's Hospital, 1 Shing Cheong Road, Kowloon Bay, Hong Kong SAR, China.
Eur J Med Genet. 2022 Oct;65(10):104573. doi: 10.1016/j.ejmg.2022.104573. Epub 2022 Jul 31.
Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder with autosomal dominant inheritance. We performed mutation analyses on 123 Chinese patients with "definite TSC" according to the latest diagnostic criteria. Pathogenic / likely-pathogenic variants were identified in 72.2% of all index patients (70/97), in which 35.7% (25/70) had TSC1 variants and 64.3% (45/70) had TSC2 variants. 84.5% (82/97) cases were sporadic and 15.5% (15/97) cases were familial. 62 unique variants were reported, in which 41.9% (26/62) were novel. Male patients had significantly more subependymal nodules (p=0.029) than females, whereas renal angiomyolipoma (p=0.032) occurred predominantly in females. Sporadic cases also had more renal angiomyolipoma (p=0.004), cortical tubers (p=0.008), hypopigmented macules (p=0.018) and fibrous cephalic plaques (p=0.028) than cases with known inheritance. Patients with TSC2 pathogenic variants were more likely to have mental retardation (p<0.001), cardiac rhabdomyoma (p=0.004), renal angiomyolipoma (p=0.006) and facial angiofibromas (p=0.026) than those with TSC1 pathogenic variants, while mutation-negative cases showed a mixed phenotype between those with TSC1 and TSC2 variants. There were no significant phenotypic differences between patients with and without TSC1/TSC2 variants, but TSC2 missense and in-frame variants were associated with higher frequencies of mental retardation (P<0.001), renal angiomyolipoma (p=0.001), cardiac rhabdomyoma (p=0.012) and facial angiofibroma (p=0.021) than those with TSC1 frameshift and splice site variants. Furthermore, a higher frequency of mental retardation (p=0.013) was observed in patients with TSC2 missense and in-frame variants than those with frameshift and splice site variants. All 14 antenatal-onset patients had cardiac rhabdomyoma. They had fewer seizures (p=0.028) than patients with paediatric-onset, but were more likely to have mental retardation (p=0.035) than individuals with adult-onset disease. Generally, paediatric-onset patients had more neurological manifestations, while initial presentations of adult-onset TSC were more diverse.
结节性硬化症 (TSC) 是一种常染色体显性遗传的多系统神经皮肤疾病。我们根据最新的诊断标准对 123 名“明确 TSC”的中国患者进行了突变分析。在所有索引患者中，确定了致病性/可能致病性变异 72.2%（70/97），其中 35.7%（25/70）为 TSC1 变异，64.3%（45/70）为 TSC2 变异。84.5%（97 例）为散发性，15.5%（97 例）为家族性。共报道了 62 个独特的变异，其中 41.9%（26/62）为新变异。男性患者的室管膜下结节明显多于女性（p=0.029），而女性更容易发生肾血管平滑肌脂肪瘤（p=0.032）。散发性病例也比已知遗传病例更容易发生肾血管平滑肌脂肪瘤（p=0.004）、皮质结节（p=0.008）、色素减退斑（p=0.018）和纤维性颅面斑块（p=0.028）。与 TSC1 致病性变异相比，携带 TSC2 致病性变异的患者更容易发生智力障碍（p<0.001）、心脏横纹肌瘤（p=0.004）、肾血管平滑肌脂肪瘤（p=0.006）和面部血管纤维瘤（p=0.026），而无突变的病例则显示出介于 TSC1 和 TSC2 变异之间的混合表型。有和没有 TSC1/TSC2 变异的患者之间没有显著的表型差异，但 TSC2 错义和框内变异与智力障碍（P<0.001）、肾血管平滑肌脂肪瘤（p=0.001）、心脏横纹肌瘤（p=0.012）和面部血管纤维瘤（p=0.021）的频率更高有关，而 TSC1 移码和剪接位点变异则不然。此外，与 TSC1 移码和剪接位点变异相比，携带 TSC2 错义和框内变异的患者智力障碍的发生率更高（p=0.013）。所有 14 例产前发病的患者均有心脏横纹肌瘤。与儿童发病的患者相比，他们的癫痫发作更少（p=0.028），但智力障碍的可能性更大（p=0.035）。一般来说，儿童发病的患者有更多的神经表现，而成年发病的 TSC 患者的初始表现则更为多样化。
