背景:结节性硬化症(TSC)是一种以面部血管纤维瘤为特征的常染色体显性遗传病,癫痫,智力残疾,以及几个器官错构瘤的发展,包括心脏,肾脏,大脑,还有肺.TSC1或TSC2的突变导致mTOR激活失调,导致TSC的发生。
方法:一名44岁男子因急性腰痛和血尿住院。
方法:患者出现面部血管纤维瘤,癫痫,纤维斑块,甲周纤维瘤,肾血管平滑肌脂肪瘤(AML),肺淋巴管平滑肌瘤病(LAM),肝错构瘤,和骨硬化。根据临床表现对TSC进行诊断。
方法:进行下一代测序(NGS)以筛选潜在的变异体,使用Sanger测序进行了验证。使用小基因测定法分析最终变体。
结果:使用NGS鉴定了潜在致病性的新型TSC2变体(NM_000548.4,c.336_336+15delGGTAAGGCCCAGGGCG),并使用Sanger测序进行了确认。体外小基因分析表明,变体c.336_33615delGGTAAGGCCCAGGGCG导致74bp序列错误整合到内含子4中。在他未受影响的父母或100个无关的健康对照中未发现这种新颖的变体。
结论:我们鉴定了一种新的杂合TSC2变体,c.336_336+15delGGTAAGGCCCAGGGCG,在患有经典TSC的患者中,并使用小基因测定证明该变体导致异常剪接。我们的结果扩展了对TSC2突变谱的理解。
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by facial angiofibromas, epilepsy, intellectual disability, and the development of hamartomas in several organs, including the heart, kidneys, brain, and lungs. Mutations in either TSC1 or TSC2 result in dysregulated mTOR activation, leading to the occurrence of TSC.
METHODS: A 44-year-old man was hospitalized for acute lumbago and hematuria.
METHODS: The patient presented with facial angiofibromas, epilepsy, fibrous plaques, periungual fibroma, renal angiomyolipomas (AML), pulmonary lymphangioleiomyomatosis (LAM), liver hamartomas, and osteosclerosis. A diagnosis of TSC was made based on clinical manifestations.
METHODS: Next-generation sequencing (NGS) was performed to screen for potential variants, which were verified using Sanger sequencing. The final variant was analyzed using a minigene assay.
RESULTS: A potentially pathogenic novel TSC2 variant (NM_000548.4, c.336_336 + 15delGGTAAGGCCCAGGGCG) was identified using NGS and confirmed using Sanger sequencing. The in vitro minigene assay showed that the variant c.336_336 + 15delGGTAAGGCCCAGGGCG caused erroneous integration of a 74 bp sequence into intron 4. This novel variant was not found in his unaffected parents or 100 unrelated healthy controls.
CONCLUSIONS: We identified a novel heterozygous TSC2 variant, c.336_336 + 15delGGTAAGGCCCAGGGCG, in a patient with classical TSC and demonstrated that this variant leads to aberrant splicing using a minigene assay. Our results extend the understanding of the mutational spectrum of TSC2.