PDF(Pubmed)
Abstract：
BACKGROUND: TTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants.
METHODS: Whole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed.
RESULTS: TTN c.38,876-2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases.
CONCLUSIONS: Here we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.
METHODS: Whole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed.
RESULTS: TTN c.38,876-2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases.
CONCLUSIONS: Here we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.
摘要：
背景：TTN是一种复杂的基因，具有较大的基因组大小和高度重复的结构。据报道，TTN中的致病变体会导致一系列骨骼肌和心脏疾病。纯合或复合杂合突变倾向于引起具有先天性或儿童期发作的广泛表型。特征的发作和严重程度被认为与TTN变体的类型和位置相关。
方法：对三个不相关的出现胎儿运动障碍变形序列（FADS）的家族进行全外显子组测序，主要表现为胎动减少和肢体挛缩。进行Sanger测序以确认变体。进行RT-PCR分析。
结果：TTNc.38,876-2A>C，只有元转录本的变体，具有反式的第二种致病或可能的致病变体，在三个家庭的五个受影响的胎儿中观察到。Sanger测序显示所有的胎儿变异均遗传自父母。RT-PCR分析显示两种异常剪接,包括内含子199的延伸和8个碱基的跳跃。
结论：这里我们报道了由4个TTN变异体引起的3个不相关的FADS家族。此外,我们的研究表明，仅致病性meta转录本的TTN变体可以导致缺陷，这些缺陷在产前可以隐性识别。
方法：对三个不相关的出现胎儿运动障碍变形序列（FADS）的家族进行全外显子组测序，主要表现为胎动减少和肢体挛缩。进行Sanger测序以确认变体。进行RT-PCR分析。
结果：TTNc.38,876-2A>C，只有元转录本的变体，具有反式的第二种致病或可能的致病变体，在三个家庭的五个受影响的胎儿中观察到。Sanger测序显示所有的胎儿变异均遗传自父母。RT-PCR分析显示两种异常剪接,包括内含子199的延伸和8个碱基的跳跃。
结论：这里我们报道了由4个TTN变异体引起的3个不相关的FADS家族。此外,我们的研究表明，仅致病性meta转录本的TTN变体可以导致缺陷，这些缺陷在产前可以隐性识别。
