PDF(Pubmed)
Abstract：
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss-of-function of either TSC1 or TSC2 gene. However, in 10%-15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing.
METHODS: In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single-gene tests.
RESULTS: Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3\'-end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1.
CONCLUSIONS: In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy-neutral variant was missed by the TSC1 and TSC2 single-gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.
METHODS: In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single-gene tests.
RESULTS: Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3\'-end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1.
CONCLUSIONS: In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy-neutral variant was missed by the TSC1 and TSC2 single-gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.
摘要：
背景：结节性硬化症（TSC）是一种常染色体显性遗传多系统疾病，由TSC1或TSC2基因的功能丧失引起。然而,在10％-15％的TSC患者中，根据标准的临床测试，在TSC1或TSC2基因中均未发现致病性变异。
方法：在本研究中，对临床诊断为TSC的家族进行了基因组测序,TSC1和TSC2单基因检测结果为阴性.
结果：这里，我们报告了一个家族，呈现经典的TSC表型，涉及TSC1基因的复杂结构变异：染色体9长臂中的染色体内反向插入。我们推测反向9q33.3q34.13区域被插入到q31.2区域，倒位断裂点的3'端位于TSC1基因内，导致TSC1提前终止。
结论：在这项研究中，我们证明了基因组测序用于鉴定复杂染色体重排的实用性。因为断点位于深内含子/基因间区域内，TSC1和TSC2单基因检测未发现该拷贝中性变异,并导致病因未知.一起,这一发现提示复杂的结构变异可能是TSC病因被低估的原因.
方法：在本研究中，对临床诊断为TSC的家族进行了基因组测序,TSC1和TSC2单基因检测结果为阴性.
结果：这里，我们报告了一个家族，呈现经典的TSC表型，涉及TSC1基因的复杂结构变异：染色体9长臂中的染色体内反向插入。我们推测反向9q33.3q34.13区域被插入到q31.2区域，倒位断裂点的3'端位于TSC1基因内，导致TSC1提前终止。
结论：在这项研究中，我们证明了基因组测序用于鉴定复杂染色体重排的实用性。因为断点位于深内含子/基因间区域内，TSC1和TSC2单基因检测未发现该拷贝中性变异,并导致病因未知.一起,这一发现提示复杂的结构变异可能是TSC病因被低估的原因.
